Novel aryl fructose-1,6-bisphosphatase inhibitors

ABSTRACT

Novel FBPase inhibitors of the formula I  
                 
are useful in the treatment of diabetes and other conditions associated with elevated blood glucose.

RELATED APPLICATION

The present application claims the benefit of priority to U.S.Provisional Application No. 60/187,750, filed on Mar. 8, 2000 and isincorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to novel aryl containing compounds that possess aphosphonate group that are inhibitors of Fructose-1,6-bisphosphatase.The invention also relates to the preparation and use of these compoundsin the treatment of diabetes, and other diseases where the inhibition ofgluconeogenesis, control of blood glucose levels, reduction in glycogenstorage, or reduction in insulin levels is beneficial.

BACKGROUND AND INTRODUCTION TO THE INVENTION

The following description of the background of the invention is providedto aid in understanding the invention, but is not admitted to be, or todescribe, prior art to the invention. All cited publications areincorporated by reference herein in their entirety.

Diabetes mellitus (or diabetes) is one of the most prevalent diseases inthe world today. Diabetic patients have been divided into two classes,namely type I or insulin-dependent diabetes mellitus and type II ornon-insulin dependent diabetes mellitus (NIDDM). NIDDM accounts forapproximately 90% of all diabetics and is estimated to affect 12-14million adults in the U.S. alone (6.6% of the population). NIDDM ischaracterized by both fasting hyperglycemia and exaggerated postprandialincreases in plasma glucose levels. NIDDM is associated with a varietyof long-term complications, including microvascular diseases such asretinopathy, nephropathy and neuropathy, and macrovascular diseases suchas coronary heart disease. Numerous studies in animal models demonstratea causal relationship between long term hyperglycemia and complications.Results from the Diabetes Control and Complications Trial (DCCT) and theStockholm Prospective Study demonstrate this relationship for the firsttime in man by showing that insulin-dependent diabetics with tighterglycemic control are at substantially lower risk for the development andprogression of these complications. Tighter control is also expected tobenefit NIDDM patients.

Current therapies used to treat NIDDM patients entail both controllinglifestyle risk factors and pharmaceutical intervention. First-linetherapy for NIDDM is typically a tightly-controlled regimen of diet andexercise since an overwhelming number of NIDDM patients are overweightor obese (67%) and since weight loss can improve insulin secretion,insulin sensitivity and lead to normoglycemia. Normalization of bloodglucose occurs in less than 30% of these patients due to poor complianceand poor response. Patients with hyperglycemia not controlled by dietalone are subsequently treated with oral hypoglycemics or insulin. Untilrecently, the sulfonylureas were the only class of oral hypoglycemicagents available for NIDDM. Treatment with sulfonylureas leads toeffective blood glucose lowering in only 70% of patients and only 40%after 10 years of therapy. Patients that fail to respond to diet andsulfonylureas are subsequently treated with daily insulin injections togain adequate glycemic control.

Although the sulfonylureas represent a major therapy for NIDDM patients,four factors limit their overall success. First, as mentioned above, alarge segment of the NIDDM population do not respond adequately tosulfonylurea therapy (i.e. primary failures) or become resistant (i.e.secondary failures). This is particularly true in NIDDM patients withadvanced NIDDM since these patients have severely impaired insulinsecretion. Second, sulfonylurea therapy is associated with an increasedrisk of severe hypoglycemic episodes. Third, chronic hyperinsulinemiahas been associated with increased cardiovascular disease although thisrelationship is considered controversial and unproven. Last,sulfonylureas are associated with weight gain, which leads to worseningof peripheral insulin sensitivity and thereby can accelerate theprogression of the disease.

Results from the U.K. Diabetes Prospective Study also showed thatpatients undergoing maximal therapy of a sulfonylurea, metformin, or acombination of the two, were unable to maintain normal fasting glycemiaover the six year period of the study. U.K. Prospective Diabetes Study16. Diabetes, 44:1249-158.(1995). These results further illustrate thegreat need for alternative therapies.

Gluconeogenesis from pyruvate and other 3-carbon precursors is a highlyregulated biosynthetic pathway requiring eleven enzymes. Seven enzymescatalyze reversible reactions and are common to both gluconeogenesis andglycolysis. Four enzymes catalyze reactions unique to gluconeogenesis,namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase,fructose-1,6-bisphosphatase and glucose-6-phosphatase. Overall fluxthrough the pathway is controlled by the specific activities of theseenzymes, the enzymes that catalyzed the corresponding steps in theglycolytic direction, and by substrate availability. Dietary factors(glucose, fat) and hormones (insulin, glucagon, glucocorticoids,epinephrine) coordinatively regulate enzyme activities in thegluconeogenesis and glycolysis pathways through gene expression andpost-translational mechanisms.

Of the four enzymes specific to gluconeogenesis,fructose-1,6-bisphosphatase (hereinafter “FBPase”) is the most suitabletarget for a gluconeogenesis inhibitor based on efficacy and safetyconsiderations. Studies indicate that nature uses the FBPase/PFK cycleas a major control point (metabolic switch) responsible for determiningwhether metabolic flux proceeds in the direction of glycolysis orgluconeogenesis. Claus, et al., Mechanisms of Insulin Action, Belfrage,P. editor, pp.305-321, Elsevier Science 1992; Regen, et al. J. Theor.Biol., 111:635-658 (1984); Pilkis, et al. Annu. Rev. Biochem, 57:755-783(1988). FBPase is inhibited by fructose-2,6-bisphosphate in the cell.Fructose-2,6-bisphosphate binds to the substrate site of the enzyme. AMPbinds to an allosteric site on the enzyme.

Synthetic inhibitors of FBPase have also been reported. McNiel reportedthat fructose-2,6-bisphosphate analogs inhibit FBPase by binding to thesubstrate site. J. Am. Chem. Soc., 106:7851-7853 (1984); U.S. Pat. No.4,968,790 (1984). These compounds, however, were relatively weak and didnot inhibit glucose production in hepatocytes presumably due to poorcell penetration.

Gruber reported that some nucleosides can lower blood glucose in thewhole animal through inhibition of FBPase. These compounds exert theiractivity by first undergoing phosphorylation to the correspondingmonophosphate. EP 0 427 799 B1.

Gruber et al. U.S. Pat. No. 5,658,889 described the use of inhibitors ofthe AMP site of FBPase to treat diabetes. WO 98/39344, WO 98/39343, WO98/39342 and WO 00/14095 describe specific inhibitors of FBPase to treatdiabetes.

SUMMARY OF THE INVENTION

The present invention is directed towards novel aryl compoundscontaining a phosphonate or phosphoramidate group and are potent FBPaseinhibitors. In another aspect, the present invention is directed to thepreparation of this type of compound and to the in vitro and in vivoFBPase inhibitory activity of these compounds. Another aspect of thepresent invention is directed to the clinical use of these FBPaseinhibitors as a method of treatment or prevention of diseases responsiveto inhibition of gluconeogenesis and in diseases responsive to loweredblood glucose levels.

The compounds are also useful in treating or preventing excess glycogenstorage diseases and diseases such as cardiovascular diseases includingatherosclerosis, myocardial ischemic injury, and diseases such asmetabolic disorders such as hypercholesterolemia, hyperlipidemia whichare exacerbated by hyperinsulinema and hyperglycemia.

The invention also comprises the novel compounds and methods of usingthem as specified below in formula I. Also included in the scope of thepresent invention are prodrugs of the compounds of formula I.

Since these compounds may have asymmetric centers, the present inventionis directed not only to racemic mixtures of these compounds, but also toindividual stereoisomers. The present invention also includespharmaceutically acceptable and/or useful salts of the compounds offormula I, including acid addition salts. The present inventions alsoencompass prodrugs of compounds of formula I.

DETAILED DESCRIPTION

Definitions

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

L group nomenclature as used herein in formula I begins with the groupattached to the phosphorous and ends with the group attached to the arylring. For example, when L is -alkylcarbonylamino-, the followingstructure is intended:P(O)(YR¹)₂-alk-C(O)-NR-(aromatic ring)

For J², J³, J⁴, J⁵, and J⁶ groups and other substituents of the R⁵aromatic ring, the substituents are described in such a way that theterm ends with the group attached to the aromatic ring. Generally,substituents are named such that the term ends with the group at thepoint of attachment. For example, when J² is alkylaryl, the intendedstructure is alkylaryl-G² in the ring.

The term “aryl” refers to aromatic groups which have. 5-14 ring atomsand at least one ring having a conjugated pi electron system andincludes carbocyclic aryl, heterocyclic aryl and biaryl groups, all ofwhich may be optionally substituted. Suitable aryl groups include phenyland furan-2,5-diyl.

Carbocyclic aryl groups are groups wherein the ring atoms on thearomatic ring are carbon atoms. Carbocyclic aryl groups includemonocyclic carbocyclic aryl groups and polycyclic or fused compoundssuch as optionally substituted naphthyl groups.

Heterocyclic aryl or heteroaryl groups are groups having from 1 to 4heteroatoms as ring atoms in the aromatic ring and the remainder of thering atoms being carbon atoms. Suitable heteroatoms include oxygen,sulfur, nitrogen, and selenium. Suitable heteroaryl groups includefuranyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl,pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, alloptionally substituted.

The term “biaryl” represents aryl groups containing more than onearomatic ring including both fused ring systems and aryl groupssubstituted with other aryl groups. Such groups may be optionallysubstituted. Suitable biaryl groups include naphthyl and biphenyl.

The term “alicyclic” means compounds which combine the properties ofaliphatic and cyclic compounds. Such cyclic compounds include but arenot limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds.The cyclic compound includes heterocycles. Cyclohexenylethyl andcyclohexylethyl are suitable alicyclic groups. Such groups may beoptionally substituted.

The term “optionally substituted” or “substituted” includes groupssubstituted by one to four substituents, independently selected fromlower alkyl, lower aryl, lower aralkyl, lower alicyclic, heterocyclicalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy,heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido,amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl,carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl,alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino,aralkylamino, phosphono, sulfonyl, -carboxamidoalkylaryl,-carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-,aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl,and arylalkyloxyalkyl. These optional substituents may not be optionallysubstituted. “Substituted aryl” and “substituted heteroaryl” refers toaryl and heteroaryl groups substituted with 1-3 substituents. In oneaspect, suitable substituents are selected from the group consisting oflower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.“Substituted” when describing an R⁵ group does not include annulation.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup. Suitable aralkyl groups include benzyl, picolyl, and the like,and may be optionally substituted. The term “-aralkyl-” refers to adivalent group -aryl-alkylene-. Thus, “aralkyl” is synonymous with“aralkylene.” “Heteroarylalkyl” refers to an alkylene group substitutedwith a heteroaryl group.

The term “-alkylaryl-” refers to the group -alk-aryl- where “alk” is analkylene group. Thus, “-alkylaryl-” is synonymous with “-alkylenearyl-.”“Lower -alkylaryl-” refers to such groups where alkylene is loweralkylene.

The term “lower” referred to herein in connection with organic radicalsor compounds respectively defines such as with up to and including 10,or up to and including 6, or one to four carbon atoms. Such groups maybe straight chain, branched, or cyclic.

The terms “arylamino” (a), and “aralkylamino” (b), respectively, referto the group —NRR′ wherein respectively, (a) R is aryl and R′ ishydrogen, alkyl, aralkyl or aryl, and (b) R is aralkyl and R′ ishydrogen or aralkyl, aryl, alkyl.

The term “acyl” refers to —C(O)R where R is alkyl or aryl.

The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl,aralkyl, or alicyclic, all optionally substituted.

The term “carboxyl” refers to —C(O)OH.

The term “oxo” refers to ═O in an alkyl group.

The term “amino” refers to —NRR′ where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except Hare optionally substituted; and R and R′ can form a cyclic ring system.

The term “carbonylamino” and “-carbonylamino-” refers to RCONR— and—CONR—, respectively, where each R is independently hydrogen or alkyl.

The term “halogen” or “halo” refers to —F, —Cl, —Br and —I.

The term “-oxyalkylamino-” refers to —O-alk-NR—, where “alk” is analkylene group and R is H or alkyl. Thus, “-oxyalkylamino-” issynonymous with “-oxyalkyleneamino-.”

The term “-alkylaminoalkylcarboxy-” refers to the group-alk-NR-alk-C(O)—O— where “alk” is an alkylene group, and R is a H orlower alkyl. Thus, “-alkylaminoalkylcarboxy-” is synonymous with“-alkyleneaminoalkylenecarboxy-.”

The term “-alkylaminocarbonyl-” refers to the group -alk-NR—C(O)— where“alk” is an alkylene group, and R is a H or lower alkyl. Thus,“-alkylaminocarbonyl-” is synonymous with “-alkyleneaminocarbonyl-.”

The term “-oxyalkyl-” refers to the group —O-alk- where “alk” is analkylene group. Thus, “-oxyalkyl-” is synonymous with “-oxyalkylene-.”

The term “-alkylcarboxyalkyl-” refers to the group -alk-C(O)—O-alk-where each alk is independently an alkylene group. Thus,“-alkylcarboxyalkyl-” is synonymous with “-alkylenecarboxyalkylene-.”

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched chain and cyclic groups. Alkyl groups may beoptionally substituted. Suitable alkyl groups include methyl, isopropyl,and cyclopropyl.

The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that arecyclic groups of 3 to 6 or 3 to 10 atoms. Suitable cyclic groups includenorbornyl and cyclopropyl. Such groups may be substituted.

The term “heterocyclic” and “heterocyclic alkyl” refer to cyclic groupsof 3 to 6 atoms, or 3 to 10 atoms, containing at least one heteroatom.In one aspect, these groups contain 1 to 3 heteroatoms. Suitableheteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groupsmay be attached through a nitrogen or through a carbon atom in the ring.Suitable heterocyclic groups include pyrrolidinyl, morpholino,morpholinoethyl, and pyridyl. Such groups may be substituted.

The term “phosphono” refers to —PO₃R₂, where R is selected from thegroup consisting of —H, alkyl, aryl, aralkyl, and alicyclic.

The term “sulphonyl” or “sulfonyl” refers to —S(O)₂OR, where R isselected from the group of H, alkyl, aryl, aralkyl, or alicyclic.

The term “alkenyl” refers to unsaturated groups which contain at leastone carbon-carbon double bond and includes straight-chain,branched-chain and cyclic groups. Alkenyl groups may be optionallysubstituted. Suitable alkenyl groups include allyl. “1-alkenyl” refersto alkenyl groups where the double bond is between the first and secondcarbon atom. If the 1-alkenyl group is attached to another group, e.g.it is a W substituent attached to the cyclic phosphonate orphosphoramidate, it is attached at the first carbon.

The term “alkynyl” refers to unsaturated groups which contain at leastone carbon-carbon triple bond and includes straight-chain,branched-chain and cyclic groups. Alkynyl groups may be optionallysubstituted. Suitable alkynyl groups include ethynyl. “1-alkynyl” refersto alkynyl groups where the triple bond is between the first and secondcarbon atom. If the 1-alkynyl group is attached to another group, e.g.it is a W substituent attached to the cyclic phosphonate orphosphoramidate, it is attached at the first carbon.

The term “alkylene” refers to a divalent straight chain, branched chainor cyclic saturated aliphatic group.

The term “-cycloalkylene-COOR³” refers to a divalent cyclic alkyl groupor heterocyclic group containing 4 to 6 atoms in the ring, with 0-1heteroatoms selected from O, N, and S. The cyclic alkyl or heterocyclicgroup is substituted with —COOR³.

The term “acyloxy” refers to the ester group —O—C(O)R, where R is H,alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.

The term “aminoalkyl-” refers to the group NR₂-alk- wherein “alk” is analkylene group and R is selected from the group of H, alkyl, aryl,aralkyl, and alicyclic.

The term “alkylaminoalkyl-” refers to the group alkyl-NR-alk- whereineach “alk” is an independently selected alkylene, and R is H or loweralkyl. Thus, “alkylaminoalkyl-” is synonymous with“alkylaminoalkylene-.” “Lower alkylaminoalkyl-” refers to groups whereeach alkylene group is lower alkylene.

The term “arylaminoalkyl-” refers to the group aryl-NR-alk- wherein“alk” is an alkylene group and R is H, alkyl, aryl, aralkyl, andalicyclic. Thus, “arylaminoalkyl-” is synonymous with“arylaminoalkylene-.” In “lower arylaminoalkyl-”, the alkylene group islower alkylene.

The term “alkylaminoaryl-” refers to the group alkyl-NR-aryl- wherein“aryl” is a divalent group and R is H, alkyl, aralkyl, and alicyclic. In“lower alkylaminoaryl-”, the alkyl group is lower alkyl.

The term “alkyloxyaryl-” refers to an aryl group substituted with analkyloxy group. In “lower alkyloxyaryl-”, the alkyl group is loweralkyl.

The term “aryloxyalkyl-” refers to an alkyl group substituted with anaryloxy group. Thus, “aryloxyalkyl-” is synonymous with“aryloxyalkylene-.”

The term “aralkyloxyalkyl-” refers to the group aryl-alk-O-alk- wherein“alk” is an alkylene group. Thus, “aralkyloxyalkyl-” is synonymous with“aralkyloxyalkylene-.” “Lower aralkyloxyalkyl-” refers to such groupswhere the alkylene groups are lower alkylene.

The term “-alkoxy-” or “-alkyloxy-” refers to the group -alk-O— wherein“alk” is an alkylene group. Thus, “-alkoxy-” and “-alkyloxy-” aresynonymous with “-alkyleneoxy-.” The term “alkoxy-” refers to the groupalkyl-O—.

The term “-alkoxyalkyl-” or “-alkyloxyalkyl-” refer to the group-alk-O-alk- wherein each “alk” is an independently selected alkylenegroup. Thus, “-alkoxyalkyl-” and “-alkyloxyalkyl-” are synonymous with“-alkyleneoxyalkylene-.” In “lower -alkoxyalkyl-”, each alkylene islower alkylene.

The terms “alkylthio-” and “-alkylthio-” refer to the groups alkyl-S—,and -alk-S—, respectively, wherein “alk” is alkylene group. Thus,“-alkylthio-” is synonymous with “-alkylenethio-.”

The term “-alkylthioalkyl-” refers to the group -alk-S-alk- wherein each“alk” is an independently selected alkylene group. Thus,“-alkylthioalkyl-” is synonymous with “-alkylenethioalkylene-.” In“lower -alkylthioalkyl-” each alkylene is lower alkylene.

The term “alkoxycarbonyloxy-” refers to alkyl-O—C(O)—O—.

The term “aryloxycarbonyloxy-” refers to aryl-O—C(O)—O—.

The term “alkylthiocarbonyloxy-” refers to alkyl-S—C(O)—O—.

The term “-alkoxycarbonylamino-” refers to -alk-O—C(O)—NR¹—, where “alk”is alkylene and R¹ includes —H, alkyl, aryl, alicyclic, and aralkyl.Thus, “-alkoxycarbonylamino-” is synonymous with“-alkyleneoxycarbonylamino-.”

The term “-alkylaminocarbonylamino-” refers to -alk-NR¹—C(O)—NR¹—, where“alk” is alkylene and R¹ is independently selected from H, alkyl, aryl,aralkyl, and alicyclic. Thus, “-alkylaminocarbonylamino-”is synonymouswith “-alkyleneaminocarbonylamino-.”

The terms “amido” or “carboxamido” refer to NR₂—C(O)— and RC(O)—NR¹—,where R and R¹ include H, alkyl, aryl, aralkyl, and alicyclic. The termdoes not include urea, —NR—C(O)—NR—.

The terms “carboxamidoalkylaryl” and “carboxamidoaryl” refer to anar-alk-NR¹—C(O)—, and ar-NR¹—C(O)—, respectively, where “ar” is aryl,and “alk” is alkylene, R¹ and R include H, alkyl, aryl, aralkyl, andalicyclic. Thus, “carboxamidoalkylaryl” is synonymous with“carboxamidoalkylenearyl.”

The term “-alkylcarboxamido-” or “-alkylcarbonylamino-” refers to thegroup -alk- C(O)N(R)— wherein “alk” is an alkylene group and R is H orlower alkyl. Thus, “-alkylcarboxamido-” and “-alkylcarbonylamino-” aresynonymous with “-alkylenecarboxamido-” and “-alkylenecarbonylamino-,”respectively.

The term “-alkylaminocarbonyl-” refers to the group -alk-NR—C(O)—wherein “alk” is an alkylene group and R is H or lower alkyl. Thus,“-alkylaminocarbonyl-” is synonymous with “-alkyleneaminocarbonyl-.”

The term “aminocarboxamidoalkyl-” refers to the group NR₂—C(O)—N(R)-alk-wherein R is an alkyl group or H and “alk” is an alkylene group. Thus,“aminocarboxamidoalkyl-” is synonymous with “aminocarboxamidoalkylene-.”“Lower aminocarboxamidoalkyl-” refers to such groups wherein “alk” islower alkylene.

The term “thiocarbonate” refers to —O—C(S)—O— either in a chain or in acyclic group.

The term “hydroxyalkyl” refers to an alkyl group substituted with one—OH.

The term “haloalkyl” refers to an alkyl group substituted with one halo,selected from the group I, Cl, Br, F.

The term “cyano” refers to —C≡N.

The term “nitro” refers to —NO₂.

The term “acylalkyl” refers to an alkyl-C(O)-alk-, where “alk” isalkylene. Thus, “acylalkyl” is synonymous with “acylalkylene.”

The term “heteroarylalkyl” refers to an alkyl group substituted with aheteroaryl group.

The term “perhalo” refers to groups wherein every C—H bond has beenreplaced with a C-halo bond on an aliphatic or aryl group. Suitableperhaloalkyl groups include —CF₃ and —CFCl₂.

The term “guanidino” refers to both —NR—C(NR)—NR₂ as well as —N═C(NR₂)₂where each R group is independently selected from the group of —H,alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except —H areoptionally substituted.

The term “amidino” refers to —C(NR)—NR₂ where each R group isindependently selected from the group of —H, alkyl, alkenyl, alkynyl,aryl, and alicyclic, all except —H are optionally substituted.

The term “pharmaceutically acceptable salt” includes salts of compoundsof formula I and its prodrugs derived from the combination of a compoundof this invention and an organic or inorganic acid or base. Suitableacids include hydrochloric acid, hydrobromic acid, acetic acid,trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid andmaleic acid.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the “drug” substance (abiologically active compound) in or more steps involving spontaneouschemical reaction(s), enzyme catalyzed chemical reaction(s), or both.Standard prodrugs are formed using groups attached to functionality,e.g. HO—, HS—, HOOC—, R₂N—, associated with the FBPase inhibitor, thatcleave in vivo. Prodrugs for these groups are well known in the art andare often used to enhance oral bioavailability or other propertiesbeneficial to the formulation, delivery, or activity of the drug.Standard prodrugs include but are not limited to carboxylate esterswhere the group is alkyl, aryl, aralkyl, acyloxyalkyl,alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amineswhere the group attached is an acyl group, an alkoxycarbonyl,aminocarbonyl, phosphate or sulfate. Standard prodrugs of phosphonicacids are also included and may be represented by R¹ in formula I. Thegroups illustrated are exemplary, not exhaustive, and one skilled in theart could prepare other known varieties of prodrugs. Such prodrugs ofthe compounds of formula I fall within the scope of the presentinvention. Prodrugs must undergo some form of a chemical transformationto produce the compound that is biologically active. In some cases, theprodrug is biologically active usually less than the drug itself, andserves to improve efficacy or safety through improved oralbioavailability, pharmacodynamic half-life, etc.

The term “prodrug ester” as employed herein refers to esters ofphosphonic acids or phosphoramic acids and includes, but is not limitedto, the following groups and combinations of these groups:

[1] Acyloxyalkyl esters which are well described in the literature(Farquhar et al., J. Pharm. Sci. 72, 324-325 (1983)) and are representedby formula A

wherein R, R′, and R″ are independently H, alkyl, aryl, alkylaryl, andalicyclic; (see WO 90/08155; WO 90/10636).

[2] Other acyloxyalkyl esters are possible in which an alicyclic ring isformed such as shown in formula B. These esters have been shown togenerate phosphorus-containing nucleotides inside cells through apostulated sequence of reactions beginning with deesterification andfollowed by a series of elimination reactions (e.g. Freed et al.,Biochem. Pharm. 38: 3193-3198 (1989)).

-   -   wherein R is —H, alkyl, aryl, alkylaryl, alkoxy, aryloxy,        alkylthio, arylthio, alkylamino, arylamino, cycloalkyl, or        alicyclic.

[3] Another class of these double esters known asalkyloxycarbonyloxymethyl esters, as shown in formula A, where R isalkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; R′, andR″ are independently H, alkyl, aryl, alkylaryl, and alicyclic, have beenstudied in the area of β-lactam antibiotics (Tatsuo Nishimura et al. J.Antibiotics, 1987, 40(1), 81-90; for a review see Ferres, H., Drugs ofToday, 1983,19, 499.). More recently Cathy, M. S., et al. (Abstract fromAAPS Western Regional Meeting, April, 1997) showed that thesealkyloxycarbonyloxymethyl ester prodrugs on(9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable up to30% in dogs.

[4] Aryl esters have also been used as phosphonate prodrugs (e.g. Erion,DeLambert et al., J. Med. Chem. 37: 498, 1994; Serafinowska et al., J.Med. Chem. 38: 1372, 1995). Phenyl as well as mono and poly-substitutedphenyl proesters have generated the parent phosphonic acid in studiesconducted in animals and in man (Formula C). Another approach has beendescribed where Y is a carboxylic ester ortho to the phosphate. Khamneiand Torrence, J. Med. Chem.; 39:4109-4115 (1996).

wherein: Y is H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen,amino, alkoxycarbonyl, hydroxy, cyano, and alicyclic.

[5] Benzyl esters have also been reported to generate the parentphosphonic acid. In some cases, using substituents at the para-positioncan accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or4-alkyloxy group [Formula D, X=H, OR or O(CO)R or O(CO)OR] can generatethe 4-hydroxy compound more readily through the action of enzymes, e.g.oxidases, esterases, etc. Examples of this class of prodrugs aredescribed in Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992);Brook, et al. WO 91/19721.

wherein X and Y are independently H, alkyl, aryl, alkylaryl, alkoxy,acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl;and

-   -   R′ and R″ are independently H, alkyl, aryl, alkylaryl, halogen,        and alicyclic.

[6] Thio-containing phosphonate proesters have been described that areuseful in the delivery of FBPase inhibitors to hepatocytes. Theseproesters contain a protected thioethyl moiety as shown in formula E.One or more of the oxygens of the phosphonate can be esterified. Sincethe mechanism that results in de-esterification requires the generationof a free thiolate, a variety of thiol protecting groups are possible.For example, the disulfide is reduced by a reductase-mediated process(Puech et al., Antiviral Res., 22: 155-174 (1993)). Thioesters will alsogenerate free thiolates after esterase-mediated hydrolysis. Benzaria, etal., J. Med. Chem., 39:4958 (1996). Cyclic analogs are also possible andwere shown to liberate phosphonate in isolated rat hepatocytes. Thecyclic disulfide shown below has not been previously described and isnovel.

-   -   wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,        aryloxycarbonyl, or alkylthio.

Other examples of suitable prodrugs include proester classes exemplifiedby Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al. (J.Med. Chem. 38, 1372 (1995)); Starrett et al. (J. Med. Chem. 37, 1857(1994)); Martin et al. J. Pharm. Sci. 76, 180 (1987); Alexander et al.,Collect. Czech. Chem. Commun, 59, 1853 (1994)); and EPO patentapplication 0 632 048 A1. Some of the structural classes described areoptionally substituted, including fused lactones attached at the omegaposition (formulae E-1 and E-2) and optionally substituted2-oxo-1,3-dioxolenes attached through a methylene to the phosphorusoxygen (formula E-3) such as:

-   -   wherein R is —H, alkyl, cycloalkyl, or alicyclic; and    -   wherein Y is —H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy,        halogen, amino, alicyclic, and alkoxycarbonyl.

The prodrugs of Formula E-3 are an example of “optionally substitutedalicyclic where the cyclic moiety contains a carbonate orthiocarbonate.”

[7] Propyl phosphonate proesters can also be used to deliver FBPaseinhibitors into hepatocytes. These proesters may contain a hydroxyl andhydroxyl group derivatives at the 3-position of the propyl group asshown in formula F. The R and X groups can form a cyclic ring system asshown in formula F. One or more of the oxygens of the phosphonate can beesterified.

wherein R is alkyl, aryl, heteroaryl;

-   -   X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy; and    -   Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio,        halogen, hydrogen, hydroxy, acyloxy, amino.

[8] Phosphoramidate derivatives have been explored as phosphate prodrugs(e.g. McGuigan et al., J. Med. Chem., 1999, 42: 393 and references citedtherein) as shown in Formula G and H.

Cyclic phosphoramidates have also been studied as phosphonate prodrugsbecause of their speculated higher stability compared to non-cyclicphosphoramidates (e.g. Starrett et al., J. Med. Chem., 1994, 37: 1857.

Another type of nucleotide prodrug was reported as the combination ofS-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides& Nucleotides, 1999, 18, 981) as shown in Formula I.

Other prodrugs are possible based on literature reports such assubstituted ethyls for example, bis(trichloroethyl)esters as disclosedby McGuigan, et al. Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and thephenyl and benzyl combined nucleotide esters reported by Meier, C. etal. Bioorg. Med. Chem. Lett., 7:99-104 (1997).The structure

has a plane of symmetry running through the phosphorus-oxygen doublebond when R⁶═R⁶, V═W, and V and W are either both pointing up or bothpointing down. The same is true of structures where each —NR⁶ isreplaced with —O—. The stereochemistry where V is trans to thephosphorus-oxygen double bond is envisioned.

The term “cyclic 1′,3′-propane ester”, “cyclic 1,3-propane ester”,“cyclic 1′,3′-propanyl ester”, and “cyclic 1,3-propanyl ester” refers tothe following:

The phrase “together V² and Z² are connected via an Additional 3-5 atomsto form a cyclic group containing 5-7 ring atoms, optionally containing1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms fromboth Y groups attached to the phosphorus” includes the following:

The structure shown above (left) has an additional 3 carbon atoms thatforms a five member cyclic group. Such cyclic groups must possess thelisted substitution to be oxidized.

The phrase “together V and Z are connected via an additional 3-5 atomsto form a cyclic group, optionally containing one heteroatom, saidcyclic group is fused to an aryl group at the beta and gamma position tothe Y adjacent to V includes the following:

The phrase “together V and W are connected via an additional 3 carbonatoms to form an optionally substituted cyclic group containing 6 carbonatoms and substituted with one substituent selected from the groupconsisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy,and aryloxycarbonyloxy, attached to one of said additional carbon atomsthat is three atoms from a Y attached to the phosphorus” includes thefollowing:

The structure above has an acyloxy substituent that is three carbonatoms from a Y, and an optional substituent, —CH₃, on the new 6-memberedring. There has to be at least one hydrogen at each of the followingpositions: the carbon attached to Z; both carbons alpha to the carbonlabeled “3”; and the carbon attached to “OC(O)CH₃” above.

The phrase “together W and W′ are connected via an additional 2-5 atomsto form a cyclic group, optionally containing 0-2 heteroatoms, and Vmust be aryl, substituted aryl, heteroaryl, or substituted heteroaryl”includes the following:

The structure above has V=aryl, a spiro-fused cyclopropyl group for Wand W′, and Z=H.

The term “cyclic phosphonate” or “cyclic phosphoramidate” refers to

where together R¹ and R¹ are

where Y is independently —O— or —NR⁶—. The carbon attached to Z′ musthave a C—H bond.

The term “enhancing” refers to increasing or improving a specificproperty.

The term “enhanced oral bioavailability” refers to an increase of atleast 50% of the absorption of the dose of the parent drug or prodrug(not of this invention) from the gastrointestinal tract. In some casesit is at least 100%. Measurement of oral bioavailability usually refersto measurements of the prodrug, drug, or drug metabolite in blood,tissues, or urine following oral administration compared to measurementsfollowing systemic administration.

The term “parent drug” refers to any compound which delivers the samebiologically active compound. The parent drug form is P(O)(OH)₂-L-R⁵ andstandard prodrugs, such as esters.

The term “drug metabolite” refers to any compound produced in vivo or invitro from the parent drug, which can include the biologically activedrug.

The term “biologically active drug or agent” refers to the chemicalentity that produces a biological effect. Thus, active drugs or agentsinclude compounds which as P(O)(OH)₂-L-R⁵ are biologically active.

The term “therapeutically effective amount” refers to an amount that hasany beneficial effect in treating a disease or condition.

Compounds of Formula I

Suitable alkyl groups include groups having from 1 to about 20 carbonatoms. Suitable aryl groups include groups having from 1to about 20carbon atoms. Suitable aralkyl groups include groups having from 2 toabout 21 carbon atoms. Suitable acyloxy groups include groups havingfrom 1 to about 20 carbon atoms. Suitable alkylene groups include groupshaving from 1 to about 20 carbon atoms. Suitable alicyclic groupsinclude groups having 3 to about 20 carbon atoms. Suitable heteroarylgroups include groups having from 1 to about 20 carbon atoms and from 1to 4 heteroatoms, independently selected from nitrogen, oxygen,phosphorous, and sulfur. Suitable heteroalicyclic groups include groupshaving from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms,independently selected from nitrogen, oxygen, phosphorous, and sulfur.

In the method claims, representative are the following compounds offormula (I):

wherein R⁵ is selected from the group consisting of:

wherein:

-   -   G² is selected from the group consisting of C, O, and S;    -   G³ and G⁴ are independently selected from the group consisting        of C, N, O, and S;    -   wherein a) not more than one of G², G³, and G⁴ may be O, or        S; b) when G² is O or S, not more than one of G³ and G⁴ is N; c)        at least one of G², G³, and G⁴ is C; and d) G², G³, and G⁴ are        not all C;    -   X³, X⁴, and X⁵ are independently selected from the group        consisting of C and N, wherein no more than two of X³, X⁴, and        X⁵ may be N;    -   J², J³, J⁴, J⁵, and J⁶ are independently selected from the group        consisting of —H, —NR⁴ ₂, —CONR⁴ ₂, —CO₂R³, halo, —S(O)₂NR⁴ ₂,        —S(O)R³, —SO₂R³, alkyl, alkenyl, alkynyl, alkylaryl,        perhaloalkyl, haloalkyl, aryl, heteroaryl, alkylene-OH,        —C(O)R¹¹, —OR , -alkylene-NR⁴ ₂, -alkylene-CN, —CN, —C(S)NR⁴ ₂,        —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, and —NR¹⁸COR²;    -   L is selected from the group consisting of:    -   i) a linking group having 2-4 atoms measured by the fewest        number of atoms connecting the carbon of the aromatic ring and        the phosphorus atom and is selected from the group consisting of        -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,        -phenyl-, -pyrimidinyl-, -pyrazinyl-, and -alkynyl-, all of        which may be optionally substituted; and    -   ii) a linking group having 3-4 atoms measured by the fewest        number of atoms connecting the carbon of the aromatic ring and        the phosphorus atom and is selected from the group consisting of        -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-,        -alkoxy-, -alkylthio-, -alkylcarbonyloxy-, -alkyl-S(O)—,        -alkyl-S(O)₂—, and -alkoxyalkyl-, all of which may be optionally        substituted;    -   Y is independently selected from the group consisting of —O—,        and —NR⁶—;    -   when Y is —O—, then R¹ attached to —O— is independently selected        from the group consisting of —H, alkyl, optionally substituted        aryl, optionally substituted alicyclic where the cyclic moiety        contains a carbonate or thiocarbonate, optionally substituted        arylalkylene-, —C(R²)₂OC(O)NR² ₂, —NR²—C(O)—R³, —C(R²)₂—OC(O)R³,        —C(R²)₂—O—C(O)OR³, —C(R²)₂OC(O)SR³, -alkyl-S—C(O)R³,        -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,    -   when one Y is —NR⁶—, and R¹ attached to it is        —(CR¹²R¹³)_(n)—C(O)—R¹⁴, then the other —YR¹ is selected from        the group consisting of —NR¹⁵R¹⁶, —OR⁷, and        NR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴;    -   or when either Y is independently selected from —O— and NR⁶—,        then together R¹ and R¹ are -alkyl-S—S-alkyl- to form a cyclic        group, or together R¹ and R¹ are        wherein        a) V is selected from the group of aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl;    -   Z is selected from the group of —CHR²OH , —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OC(S)OR³, —CHR²OC(O)SR³, —CHR²OCO₂R³, —OR²,        —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR² ₂)OH,        —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, —SCOR³, —SCO₂R³,        —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and        —(CH₂)_(p)—SR¹⁹; or    -   together V and Z are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing 1 heteroatom, said        cyclic group is fused to an aryl group at the beta and gamma        position to the Y adjacent to V; or    -   together Z and W are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing one heteroatom, and V        must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl; or    -   W and W′ are independently selected from the group of —H, alkyl,        aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or    -   together W and W′ are connected via an additional 2-5 atoms to        form a cyclic group, optionally containing 0-2 heteroatoms, and        V must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl; or        b) V², W² and W″ are independently selected from the group of        —H, alkyl, aralkyl, alicyclic, aryl, substituted, aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³,        —CH(aryl)OH, —CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR², —CH₂NHaryl,        —CH₂aryl; or    -   together V² and Z² are connected via an additional 3-5 atoms to        form a cyclic group containing 5-7 ring atoms, optionally        containing 1 heteroatom, and substituted with hydroxy, acyloxy,        alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon        atom that is three atoms from a Y attached to phosphorus;        c) Z′ is selected from the group of —OH, —OC(O)R³, —OCO₂R³, and        —OC(O)SR³;    -   D′ is —H;    -   D″ is selected from the group of —H, alkyl, —OR², —OH, and        —OC(O)R³;    -   each W³ is independently selected from the group consisting of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   p is an integer 2 or 3;    -   with the provisos that:    -   a) V, Z, W, W′ are not all —H and V², Z², W², W″ are not all —H;        and    -   R² is selected from the group consisting of R³ and —H;    -   R³ is selected from the group consisting of alkyl, aryl,        alicyclic, and aralkyl;    -   each R⁴ is independently selected from the group consisting of        —H, alkyl, -alkylenearyl, and aryl, or together R⁴ and R⁴ are        connected via 2-6 atoms, optionally including one heteroatom        selected from the group consisting of O, N, and S;    -   R⁶ is selected from the group consisting of —H, lower alkyl,        acyloxyalkyl, aryl, aralkyl, alkoxycarbonyloxyalkyl, and lower        acyl, or together with R¹² is connected via 1-4 carbon atoms to        form a cyclic group;    -   R⁷ is lower R³;    -   each R⁹ is independently selected from the group consisting of        —H, alkyl, aralkyl, and alicyclic, or together R⁹ and R⁹ form a        cyclic alkyl group;    -   R¹¹ is selected from the group consisting of alkyl, aryl, —NR²,        and —OR²; and    -   each R¹¹ and R¹³ is independently selected from the group        consisting of H, lower alkyl, lower aryl, lower aralkyl, all        optionally substituted, or R¹² and R¹³ together are connected        via a chain of 2-6 atoms, optionally including 1 heteroatom        selected from the group consisting of O, N, and S, to form a        cyclic group;    -   each R¹⁴ is independently selected from the group consisting of        —OR¹⁷, —N(R¹⁷)₂, —NHR¹⁷, —SR¹⁷, and —NR²OR²⁰;    -   R¹⁵ is selected from the group consisting of —H, lower aralkyl,        lower aryl, lower aralkyl, or together with R¹⁶ is connected via        2-6 atoms, optionally including 1 heteroatom selected from the        group consisting of O, N, and S;    -   R¹⁶ is selected from the group consisting of        —(CR¹²R¹³)_(n)—C(O)—R¹⁴, —H, lower alkyl, lower aryl, lower        aralkyl, or together with R¹⁵ is connected via 2-6 atoms,        optionally including 1 heteroatom selected from the group        consisting of O, N, and S;    -   each R¹⁷ is independently selected from the group consisting of        lower alkyl, lower aryl, and lower aralkyl, or together R¹⁷ and        R¹⁷ on N is connected via 2-6 atoms, optionally including 1        heteroatom selected from the group consisting of O, N, and S;    -   R¹⁸ is selected from the group consisting of —H and lower R³;    -   R¹⁹ is selected from the group consisting of —H, and lower acyl;    -   R²⁰ is selected from the group consisting of —H, lower R³, and        —C(O)-(lower R³);    -   n is an integer from 1 to 3;    -   with the provisos that:        -   1) when X³, X⁴, or X⁵ is N, then the respective J³, J⁴, or            J⁵ is null;        -   2) when G², G³, or G⁴ is O or S, then the respective J², J³,            or J⁴ is null;        -   3) when G³ or G⁴ is N, then the respective J³ or J⁴ is not            halogen or a group directly bonded to G³ or G⁴ via a            heteroatom;        -   4) if both Y groups are —NR⁶—; and R¹ and R¹ are not            connected to form a cyclic phosphoramidate, then at least            one R¹ is —(CR¹²R¹³)_(n)—C(O)—R¹⁴;    -   5) R¹ can be selected from the lower alkyl only when the other        YR¹ is —NR⁶—C(R¹²R¹³)_(n)—C(O)R¹⁴;    -   and pharmaceutically acceptable prodrugs and salts thereof.

In the method claims, suitable L groups include

-   -   i) a linking group having 2-4 atoms measured by the fewest        number of atoms connecting the carbon of the aromatic ring and        the phosphorus atom and is selected from the group consisting of        -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,        -pyrimidinyl-, -pyrazinyl-, and -alkynyl-, all of which may be        optionally substituted; and    -   ii) a linking group having 3-4 atoms measured by the fewest        number of atoms connecting the carbon of the aromatic ring and        the phosphorus atom and is selected from the group consisting of        -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-,        -alkoxy-, -alkylthio-, -alkylcarbonyloxy-, -alkyl-S(O)—,        -alkyl-S(O)₂—, and -alkoxyalkyl-, all of which may be optionally        substituted;

In one aspect of the invention in the method claims and in the compoundclaims are the following compounds:

wherein R⁵ is selected from the group consisting of:

wherein:

-   -   G² is selected from the group consisting of C, O, and S;    -   G³ and G⁴ are independently selected from the group consisting        of C, N, O, and S; wherein a) not more than one of G², G³, and        G⁴ may be O, or S; b) when G² is O or S, not more than one of G³        and G⁴ is N; c) at least one of G², G³, and G⁴ is C; and d) G²,        G³, and G⁴ are not all C;    -   X³, X⁴, and X⁵ are independently selected from the group        consisting of C and N, wherein no more than two of X³, X⁴, and        X⁵ may be N;    -   J², J³, J⁴, J⁵, and J⁶ are independently selected from the group        consisting of —H, —NR⁴ ₂, —CONR⁴ ₂, —CO₂R³, halo, —S(O)₂NR⁴ ₂,        —S(O)R³, —SO₂R³, alkyl, alkenyl, alkynyl, alkylaryl,        perhaloalkyl, haloalkyl, aryl, heteroaryl, alkylene-OH,        —C(O)R¹¹, —OR¹¹, -alkylene-NR⁴ ₂, -alkylene-CN, —CN, —C(S)NR⁴ ₂,        —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, and —NR¹⁸COR²;    -   L is selected from the group consisting of:    -   i) a linking group having 2-4 atoms measured by the fewest        number of atoms connecting the carbon of the aromatic ring and        the phosphorus atom and is selected from the group consisting of        -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,        -phenyl-, -pyrimidinyl-, -pyrazinyl-, and -alkynyl-, all of        which may be optionally substituted; and    -   ii) a linking group having 3-4 atoms measured by the fewest        number of atoms connecting the carbon of the aromatic ring and        the phosphorus atom and is selected from the group consisting of        -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-,        -alkoxy-, and -alkoxyalkyl-, all of which may be optionally        substituted;    -   Y is independently selected from the group consisting of —O—,        and —NR⁶—;    -   when Y is —O—, then R¹ attached to —O— is independently selected        from the group consisting of —H, alkyl, optionally substituted        aryl, optionally substituted alicyclic where the cyclic moiety        contains a carbonate or thiocarbonate, optionally substituted        arylalkylene-, —C(R²)₂OC(O)NR² ₂, —NR²—C(O)—R³, —C(R²)₂—OC(O)R³,        —C(R²)₂—O—C(O)³, —C(R²)₂OC(O)SR³, -alkyl-S—C(O)R³,        -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy,    -   when one Y is —N⁶—, and R¹ attached to it is        —(CR¹²R¹³)_(n)—C(O)—R¹⁴, then the other YR¹ is selected from the        group consisting of —NR¹⁵R¹⁶, —OR⁷, and        NR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴;    -   or when either Y is independently selected from —O— and —NR⁶—,        then together R¹ and R¹ are -alkyl-S—S-alkyl- to form a cyclic        group, or together R¹ and R¹ are        a) V is selected-from the group of aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl;    -   Z is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OC(S)OR³, —CHR²OC(O)SR³, —CHR²OCO₂R³, —OR²,        —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR² ₂)OH,        —CH(C≡CR²)OH, —R² , NR² ₂, —OCOR³, —OCO₂R³, —SCOR³, —SCO₂R³,        —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and        —(CH₂)_(p)—SR¹⁹; or    -   together V and Z are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing 1 heteroatom, said        cyclic group is fused to an aryl group at the beta and gamma        position to the Y adjacent to V; or    -   together Z and W are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing one heteroatom, and V        must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl; or    -   W and W′ are independently selected from the group of —H, alkyl,        aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or    -   together W and W′ are connected via an additional 2-5 atoms to        form a cyclic group, optionally containing 0-2 heteroatoms, and        V must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;        b) V², W² and W″ are independently selected from the group of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³,        —CH(aryl)OH, —CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR², —CH₂NHaryl,        —CH₂aryl; or    -   together V² and Z² are connected via an additional 3-5 atoms to        form a cyclic group containing 5-7 ring atoms, optionally        containing 1 heteroatom, and substituted with hydroxy, acyloxy,        alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon        atom that is three atoms from a Y attached to phosphorus;        c) Z′ is selected from the group of —OH, —OC(O)R³, —OCO₂R³, and        —OC(O)SR³;    -   D′ is —H;    -   D″ is selected from the group of —H, alkyl, —OR², —OH, and        —OC(O)R³;    -   each W³ is independently selected from the group consisting of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   p is an integer 2 or 3;    -   with the provisos that:    -   a) V, Z, W, W′ are not all —H and V², Z², W², W″ are not all —H;        and    -   R² is selected from the group consisting of R³ and —H;    -   R³ is selected from the group consisting of alkyl, aryl,        alicyclic, and aralkyl;    -   each R⁴ is independently selected from the group consisting of        —H, alkyl, -alkylenearyl, and aryl, or together R⁴ and R⁴ are        connected via 2-6 atoms, optionally including one heteroatom        selected from the group consisting of O, N, and S;    -   R⁶ is selected from the group consisting of —H, lower alkyl,        acyloxyalkyl, aryl, aralkyl, alkoxycarbonyloxyalkyl, and lower        acyl, or together with R¹² is connected via 1-4 carbon atoms to        form a cyclic group;    -   R⁷is lower R³;    -   each R⁹ is independently selected from the group consisting of        —H, alkyl, aralkyl, and alicyclic, or together R⁹ and R⁹ form a        cyclic alkyl group;    -   R 11 is selected from the group consisting of alkyl, aryl, —NR²        ₂, and —OR²; and    -   each R¹² and R¹³ is independently selected from the group        consisting of H, lower alkyl, lower aryl, lower aralkyl, all        optionally substituted, or R¹² and R¹³ together are connected        via a chain of 2-6 atoms, optionally including 1 heteroatom        selected from the group consisting of O, N, and S, to form a        cyclic group;    -   each R¹⁴ is independently selected from the group consisting of        —OR¹⁷, —N(R¹⁷)₂, —NHR¹⁷, —SR¹⁷, and —NR²OR²⁰;    -   R¹⁵ is selected from the group consisting of —H, lower aralkyl,        lower aryl, lower aralkyl, or together with R¹⁶ is connected via        2-6 atoms, optionally including 1 heteroatom selected from the        group consisting of O, N, and S;    -   R¹⁶ is selected from the group consisting of        —(CR¹²R¹³)_(n)—C(O)—R¹⁴, —H, lower alkyl, lower aryl, lower        aralkyl, or together with R¹⁵ is connected via 2-6 atoms,        optionally including 1 heteroatom selected from the group        consisting of O, N, and S;    -   each R¹⁷ is independently selected from the group consisting of        lower alkyl, lower aryl, and lower aralkyl, or together R¹⁷ and        R¹⁷ on N is connected via 2-6 atoms, optionally including 1        heteroatom selected from the group consisting of O, N, and S;    -   R¹⁸ is selected from the group consisting of —H and lower R³;    -   R¹⁹ is selected from the group consisting of —H, and lower acyl;    -   R²⁰ is selected from the group consisting of —H, lower R³, and        —C(O)-(lower R³);    -   n is an integer from 1 to 3;    -   with the provisos that:        -   1) when X³, X⁴, or X⁵ is N, then the respective J³, J⁴, or            J⁵ is null;        -   2) when L is substituted furanyl, then at least one of J²,            J³, J⁴, and J⁵ is not —H or null;        -   3) when L is not substituted furanyl, then at least two of            J², J³, J⁴, and J⁵ on formula I(a) or J², J³, J⁴, J⁵, and J⁶            on formula I(b) are not —H or null;        -   4) when G², G³, or G⁴ is O or S, then the respective J², J³,            or J⁴ is null;        -   5) when G³ or G⁴ is N, then the respective J³ or J⁴ is not            halogen or a group directly bonded to G³ or G⁴ via a            heteroatom;        -   6) if both Y groups are —NR⁶—, and R¹ and R¹ are not            connected to form a cyclic phosphoramidate, then at least            one R¹ is —(CR¹²R¹³)_(n)—C(O)—R¹⁴;        -   7) when L is -alkylcarbonylamino- or -alkylaminocarbonyl-,            then X³, X⁴, and X⁵ are not all C;        -   8) when L is -alkoxyalkyl-, and X³, X⁴, and X⁵ are all C,            then neither J³ nor J⁵ can be substituted with an acylated            amine;        -   9) when R⁵ is substituted phenyl, then J³, J⁴, and J⁵ is not            purinyl, purinylalkylene, deaza-purinyl, or            deazapurinylalkylene;        -   10) R¹ can be lower alkyl only when the other YR¹ is            —NR⁶—C(R¹²R¹³)_(n)—C(O)—R¹⁴;        -   11) when R⁵ is substituted phenyl and L is 1,2-ethynyl, then            J³ or J⁵ is not a heterocyclic group;        -   12) when L is 1,2-ethynyl, then X³ or X⁵ cannot be N;    -   and pharmaceutically acceptable prodrugs and salts thereof.

In one aspect of the present invention compounds of formula Ia areenvisioned.

In one aspect of the present invention compounds of formula Ib areenvisioned.

In one aspect of the present invention compounds of formula I areenvisioned with the further proviso that when L is -alkoxyalkyl-, and R⁵is substituted thienyl, substituted furanyl, or substituted phenyl, thenJ³, J⁴, or J⁵ s not halo or alkenyl.

In another aspect are compounds of formula I with the, further provisothat when L is -alkoxyalkyl-, then R⁵ is not substituted thienyl,substituted furanyl, or substituted phenyl.

In yet another aspect are compounds of formula I with the furtherproviso that when L is -alkoxycarbonyl-, and X³, X⁴ and X⁵ are all C,then neither J² nor J⁶ is a group attached through a nitrogen atom.

In another aspect are compounds of formula I with the further provisothat when L is -alkoxyalkyl- or -alkoxycarbonyl-, then R⁵ is notsubstituted phenyl.

In one aspect of the invention are compounds of formula I wherein saidprodrug is a compound of formula VI:

wherein

-   -   V is selected from the group consisting of aryl, substituted        aryl, heteroaryl, and substituted hetetoaryl. In another aspect        are such compounds wherein V is selected from the group        consisting of phenyl and substituted phenyl. In yet another        aspect are such compounds wherein V is selected from the group        consisting of 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl,        3-chlorophenyl, 2-bromophenyl, 3-bromophenyl, and 4-pyridyl.

In one aspect of the invention are compounds of formula I wherein saidprodrug is a compound of formula VII:

wherein

-   -   Z² is selected from the group consisting of —CHR²OH,        —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³,        —CHR²OC(S)OR³, and —CH₂aryl. In another aspect, are such        compounds wherein Z² is selected from the group consisting of        —CHR²OH, —CHR²OC(O)R³, and —CHR²OCO₂R³. In yet another aspect        are such compounds wherein R² is —H.

In another aspect of the invention are compounds of formula I whereinsaid prodrug is a compound of formula VIII:

wherein

-   -   Z′ is selected from the group consisting of —OH, —OC(O)R³,        —OCO₂R³, and —OC(O)SR³;    -   D′ is —H; and    -   D″ is selected from the group consisting of —H, alkyl, —OH, and        —OC(O)R³.

In another aspect of the invention are compounds wherein W′ and Z are—H, W and V are both the same aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl, and both Y groups are the same —NR—, such thatthe phosphonate or phosphoramidate prodrug moiety:

has a plane of symmetry through the phosphorus-oxygen double bond.

In one aspect of the invention are compounds of formula I wherein when Yis —O—, then R¹ attached to —O— is independently selected from the groupconsisting of —H, optionally substituted aryl, optionally substitutedalicyclic where the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted arlyalkylene-, —C(R²)₂OC(O)R³, —C(R²)₂—O—C(O)OR³,—C(R²)₂OC(O)SR³, -alkyl-S—C(O)R³, and -alkyl-S—S-alkylhydroxy;

-   -   when Y is —NR⁶—, then R¹ attached to —NR— is independently        selected from the group consisting of —H, and        —(CR¹²R¹³)_(n)—C(O)R¹⁴;    -   or when either Y is independently selected from —O— and —NR⁶—,        then together R¹ and R¹ are        a) V is selected from the group of aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl;    -   Z is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OC(S)OR³, —CHR²OC(O)SR³, —CHR²OCO₂R³, —OR²,        —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR² ₂)OH,        —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, SCOR³, —SCO₂R³,        —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and        —(CH₂)_(p)—SR¹⁹; or    -   together V and Z are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing 1 heteroatom, said        cyclic group is fused to an aryl group at the beta and gamma        position to the Y adjacent to V; or    -   together Z and W are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing one heteroatom, and V        must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl; or    -   W and W′ are independently selected from the group of —H, alkyl,        aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or    -   together W and W′ are connected via an additional 2-5 atoms to        form a cyclic group, optionally containing 0-2 heteroatoms, and        V must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;        b) V², W² and W″ are independently selected from the group of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³,        —CH(aryl)OH, —CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR², —CH₂NHaryl,        —CH₂aryl; or    -   together V² and Z² are connected via an additional 3-5 atoms to        form a cyclic group containing 5-7 ring atoms, optionally        containing 1 heteroatom, and substituted with hydroxy, acyloxy,        alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon        atom that is three atoms from a Y attached to phosphorus;        c) Z′ is selected from the group of —OH, —OC(O)R³, —OCO₂R³, and        —OC(O)SR³;    -   D′ is —H;    -   D″ is selected from the group of —H, alkyl, —OR², —OH, and        —OC(O)R³;    -   each W³ is independently selected from the group consisting of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   p is an integer 2 or 3;    -   with the provisos that:    -   a) V, Z, W, W′ are not all —H and V², Z², W², W″ are not all —H;        and    -   b) both Y groups are not —NR⁶—;    -   R² is selected from the group consisting of R³ and —H;    -   R³ is selected from the group consisting of alkyl, aryl,        alicyclic, and aralkyl;    -   R⁶ is selected from the group consisting of —H, and lower alkyl.

In another aspect of the invention are such compounds wherein when bothY groups are —O—, then R¹ is independently selected from the groupconsisting of optionally substituted aryl, optionally substitutedbenzyl, —C(R²)₂OC(O)R³, —C(R²)₂OC(O)OR³, and —H; or

-   -   when Y is —NR—, then the R¹ attached to said —NR⁶— group is        selected from the group consisting of —C(R⁴)₂—C(O)OR³, and        —C(R²)₂C(O)OR³; or the other Y group is —O— and then R¹ attached        to said —O— is selected from the group consisting of optionally        substituted aryl, —C(R²)₂OC(O)R³, and —C(R²)₂OC(O)OR³. Within        such group are compounds wherein both Y groups are —O—, and R¹        is H.

In another aspect of the invention are compounds wherein at least one Yis —O—, and together R¹ and R¹ are

a) V is selected: from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl;

-   -   Z is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OC(S)OR³, —CHR²OC(O)SR³, —CHR²OCO₂R³, —OR²,        —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR² ₂)OH,        —CH(C≡CR²)OH, —R² , NR² ₂, —OCOR³, —OCO₂R³, —SCOR³, —SCO₂R³,        —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and        —(CH₂)_(p)—SR¹⁹; or    -   together V and Z are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing 1 heteroatom, said        cyclic group is fused to an aryl group at the beta and gamma        position to the Y adjacent to V; or    -   together Z and W are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing one heteroatom, and V        must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl; or    -   W and W′ are independently selected from the group of —H, alkyl,        aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or    -   together W and W′ are connected via an additional 2-5 atoms to        form a cyclic group, optionally containing 0-2 heteroatoms, and        V must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;        b) V², W² and W″ are independently selected from the group of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³,        —CH(aryl)OH, —CH(CH═CR² ₂)OH, —CH(C≡CR)OH, —SR², —CH₂NHaryl,        —CH₂aryl; or    -   together V² and Z² are connected via an additional 3-5 atoms to        form a cyclic group containing 5-7 ring atoms, optionally        containing 1 heteroatom, and substituted with hydroxy, acyloxy,        alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon        atom that is three atoms from a Y attached to phosphorus;        c) Z′ is selected from the group of —OH, —OC(O)R³, —OCO₂R³, and        —OC(O)SR³;    -   D′ is —H;    -   D″ is selected from the group of —H, alkyl, —OR², —OH, and        —OC(O)R³;    -   each W³ is independently selected from the group consisting of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   p is an integer 2 or 3;    -   with the provisos that:    -   a) V, Z, W, W′ are not all —H and V², Z², W², W″ are not all —H;        and    -   b) both Y groups are not —NR⁶—;    -   R² is selected from the group consisting of R³ and —H;    -   R³ is selected from the group consisting of alkyl, aryl,        alicyclic, and aralkyl;    -   R⁶ is selected from the group consisting of —H, and lower alkyl.

In another aspect of the invention are compounds wherein one Y is —O—,and R¹ is optionally substituted aryl; and the other Y is —NR⁶—, whereR¹ attached to said —NR⁶— is selected from the group consisting of—C(R⁴)₂C(O)OR³, and —C(R²)₂C(O)OR³. In another aspect are such compoundswherein R¹ attached to —O— is selected from the group consisting ofphenyl, and phenyl substituted with 1-2 substituents selected from thegroup consisting of —NHC(O)CH₃, —F, —Cl, —Br, —C(O)OCH₂CH₃, and —CH₃;and wherein R¹ attached to —NR⁶— is —C(R²)₂C(O)OR³; each R² isindependently selected from the group consisting of —CH₃, —CH₂CH₃, and—H. Within such a group are compounds wherein the substituents of saidsubstituted phenyl are selected from the group consisting of4-NHC(O)CH₃, —Cl, —Br, 2-C(O)OCH₂CH₃, and —CH₃.

In another aspect of the invention are compounds of formula I wherein

-   -   J², J³, J⁴, J⁵, and J⁶ are independently selected from the group        consisting of —H, —NR⁴ ₂, —CONR⁴ ₂, —CO₂R³, halo, —SO₂NR⁴ ₂,        lower alkyl, lower alkenyl, lower alkylaryl, lower alkynyl,        lower perhaloalkyl, lower haloalkyl, lower aryl, lower        alkylene-OH, —OR¹¹, —CR² ₂NR⁴ ₂, —CN, —C(S)NR⁴ ₂, —OR², —SR²,        —N₃, —NO₂, —NHC(S)NR⁴ ₂, —NR¹⁸COR², —CR² ₂CN;    -   L is selected:from the group consisting of        -   i) 2,5-furanyl, 2,5-thienyl, 1,3-phenyl, 2,6-pyridyl,            2,5-oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl,            2,4-imidazolyl, 2,6-pyrimidinyl, 2,6-pyrazinyl;        -   ii) 1,2-ethynyl; and        -   iii) a linking group having 3 atoms measured by the fewest            number of atoms connecting the carbon of the aromatic ring            and the phosphorus atom and is selected from the group            consisting of alkylcarbonylamino-, -alkylaminocarbonyl-,            -alkoxycarbonyl-, and -alkoxyalkyl-;    -   when both Y groups are —O—, then R¹ is independently selected        from the group consisting of optionally substituted aryl,        optionally substituted benzyl, —C(R²)₂CO(O)R³, —C(R²)₂OC(O)OR³,        and —H; or    -   when one Y is —O—, then R¹ attached to —O— is optionally        substituted aryl; and the other Y is —NR⁶—, then R¹ attached to        —NR⁶— is selected from the group consisting of —C(R⁴)₂C(O)OR³,        and —C(R²)₂C(O)OR³; or    -   when Y is —O— or —NR⁶—, then together R¹ and R¹ are        a) V is selected from the group of aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkynyl and 1-alkenyl;    -   Z is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OC(S)OR³, —CHR²OC(O)SR³, —CHR²OCO₂R³, —OR²,        —SR², —CHR N₃, —CH₂aryl, —CH(aryl)OH, —CH(CH═CR² ₂)OH,        —CH(C≡CR²)OH, —R², NR² ₂, —OCOR³, —OCO₂R³, —SCOR³, —SCO₂R³,        —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and        —(CH₂)_(p)—SR¹⁹; or    -   together V and Z are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing 1 heteroatom, said        cyclic group is fused to an aryl group at the beta and gamma        position to the Y adjacent to V; or together Z and W are        connected via an additional 3-5 atoms to form a cyclic group,        optionally containing one heteroatom, and V must be aryl,        substituted aryl, heteroaryl, or substituted heteroaryl; or    -   W and W′ are independently selected from the group of —H, alkyl,        aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or    -   together W and W′ are connected via an additional 2-5 atoms to        form a cyclic group, optionally containing 0-2 heteroatoms, and        V must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;        b) V² W² and W″ are independently selected from the group of —H,        alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,        —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³,        —CH(aryl)OH, —CH(CH═CR² ₂)OH, —CH(C≡CR)OH, —SR², —CH₂NHaryl,        —CH₂aryl; or    -   together V² and Z² are connected via an additional 3-5 atoms to        form a cyclic group containing 5-7 ring atoms, optionally        containing 1 heteroatom, and substituted with hydroxy, acyloxy,        alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon        atom that is three atoms from a Y attached to phosphorus;        c) Z′ is selected from the group of —OH, —OC(O)R³, —OCO₂R³, and        —OC(O)SR³;    -   D′ is —H;    -   D″ is selected from the group of —H, alkyl, —OR , —OH, and        —OC(O)R³;    -   each W³ is independently selected from the group consisting of        —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;    -   p is an integer 2 or 3;    -   with the provisos that:    -   a) V, Z, W, W′ are not all —H and V², Z², W², W″ are not all —H;        and    -   b) both Y groups are not —NR⁶—;    -   R² is selected from the group consisting of R³ and —H;    -   R³ is selected from the group consisting of alkyl, aryl,        alicyclic, and aralkyl;    -   R⁶ is selected from the group consisting of —H, and lower alkyl.

In another aspect, R⁵ is substituted phenyl;

-   -   L is furan-2,5-diyl; J², J³, J⁴, J⁵, and J⁶ are independently        selected from the group consisting of —OR³, —SO₂NHR⁷, —CN, —H,        halo, —NR⁴ ₂, —(CH₂)₂aryl, —(CH₂)NH-aryl and —NO₂; at least one        Y group is —O—; and pharmaceutically acceptable salts and        prodrugs thereof.

In another aspect of the invention are such compounds wherein when Y is—O—, then R¹ attached to —O— is independently selected from the groupconsisting of —H, optionally substituted phenyl, —CH₂OC(O)-tBu,—CH₂OC(O)OEt, and —CH₂OC(O)OiPr;

-   -   when Y is —NR⁶—, then R¹ is attached to —NR⁶— independently        selected from the group consisting of —C(R²)₂C(O)OR³,        —C(R⁴)₂C(O)OR³, or    -   when Y is —O— or —NR⁶—, and at least one Y is —O—, then together        R¹ and R¹ are        wherein    -   V is selected from the group consisting of optionally        substituted aryl, and optionally substituted heteroaryl; and Z,        W′, and W are H; and    -   R is selected from the group consisting of —H, and lower alkyl.

In one aspect of the invention are compounds wherein both Y groups are—O— and R¹ is —H. In another aspect are compounds of claim 61 whereinboth Y groups are —O—, and R¹ is —CH₂OC(O)OEt. In yet another aspect arecompounds are such wherein both Y groups are —O—, and R¹ and R¹ togetherare

and V is phenyl substituted with 1-3 halogens. Within such a group arecompounds wherein V is selected from the group consisting of3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl,2-bromophenyl, and 3-bromophenyl.

In one aspect of the invention are such compounds wherein n is 1, andthe carbon attached to R¹² and R¹³ has S stereochemistry.

In another aspect of the invention are compounds wherein R¹⁵ is not H.

In yet another aspect of the invention are compounds of formula Iwherein —NR¹⁵R¹⁶is a cyclic amine. Within such a group-are compoundswherein —NR¹⁵R¹⁶ is selected from the group consisting of morpholinyland pyrrolidinyl. In another aspect of the invention, R¹⁶ groups include—(CR¹²R¹³)_(n)—C(O)—R¹⁴. In yet another aspect are compounds with theformula

Within such a group are compounds wherein n is 1. In one aspect of theinvention compounds are envisioned wherein when R¹² and R¹³ are not thesame, then R¹⁴—C(O)—CR¹⁷R¹³—N₂ is an ester or thioester of a naturallyoccurring amino acid; and R¹⁴ is selected from the group consisting of—OR¹⁷ and —SR¹⁷ .

In one aspect of the invention are compounds wherein one Y is —O— andits corresponding R¹ is optionally substituted phenyl, while the other Yis —NH—, and its corresponding R¹ is —C(R²)₂—COOR³. When R¹ is—CHR³COOR³, then the corresponding —NR⁶—*CHR³COOR³, generally has Lstereochemistry.

In general, substituents V, Z, W, W′, V², Z², W², W″, Z′, D′, D″, and W³of formula I are chosen such that they exhibit one or more of thefollowing properties:

-   -   (1) enhance the oxidation reaction since this reaction is likely        to be the rate determining step and therefore must compete with        drug elimination processes.    -   (2) enhance stability in aqueous solution and in the presence of        other non-p450 enzymes;    -   (3) enhance cell penetration, e.g. substituents are not charged        or of high molecular weight since both properties can limit oral        bioavailability as well as cell penetration;    -   (4) promote the β-elimination reaction following the initial        oxidation by producing ring-opened products that have one or        more of the following properties:        -   a) fail to recyclize;        -   b) undergo limited covalent hydration;        -   c) promote P-elimination by assisting in the proton            abstraction;        -   d) impede addition reactions that form stable adducts, e.g.            thiols to the initial hydroxylated product or nucleophilic            addition to the carbonyl generated after ring opening; and        -   e) limit metabolism of reaction intermediates (e.g.            ring-opened ketone);    -   (5) lead to a non-toxic and non-mutagenic by-product with one or        more of the following characteristics. Both properties can be        minimized by using substituents that limit Michael additions,        reactions, e.g.        -   a) electron donating Z groups that decrease double bond            polarization;        -   b) W groups that sterically block nucleophilic addition to            β-carbon;        -   c) Z groups that eliminate the double bond after the            elimination reaction either through retautomerization            (enol→keto) or hydrolysis (e.g. enamine);        -   d) V groups that contain groups that add to the            α,β-unsaturated ketone to form a ring;        -   e) Z groups that form a stable ring via Michael addition to            double bond; and        -   f) groups that enhance detoxification of the by-product by            one or more of the following characteristics:            -   (i) confine to liver; and            -   (ii) make susceptible to detoxification reactions (e.g.                ketone reduction); and    -   (6) capable of generating a pharmacologically active product.

In one aspect of the invention, V groups of formula VI are aryl,substituted aryl, heteroaryl, and substituted heteroaryl. Within such agroup aryl and substituted aryl groups include phenyl, and phenylsubstituted with 1-3 halogens. Within such a group are3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl,2-bromophenyl, and 3-bromophenyl. In another aspect of the invention, Yis —O—. In yet another aspect of the invention V is selected from thegroup consisting of monocyclic heteroaryl and monocyclic substitutedheteroaryl containing at least one nitrogen atom. Within such a groupsuch a heteroaryl and substituted heteroaryl is 4-pyridyl and3-bromopyridyl, respectively.

In yet another aspect of the invention, when together V and Z areconnected via an additional 3-5 atoms to form a cyclic group, optionallycontaining 1 heteroatom, said cyclic group is fused to an aryl group atthe beta and gamma positions to the Y attached to phosphorus. In suchcompounds it is envisioned that said aryl group may be an optionallysubstituted monocyclic aryl group and the connection between Z and thegamma position of the aryl group is selected from the group consistingof O, CH₂, CH₂CH₂, OCH₂ or CH₂O.

In another aspect, together V and W are connected via an additional 3carbon atoms to form an optionally substituted cyclic group containing 6carbon atoms and monosubstituted with one substituent selected from thegroup consisting of hydroxy, acyloxy, alkoxycarbonyloxy,alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of saidadditional carbon atoms that is three atoms from a Y attached to thephosphorus. In such compounds, it is envisioned that together V and Wmay form a cyclic group selected from the group consisting of—CH₂—CH(OH)—CH₂—, CH₂CH(OCOR³)—CH₂—, and —CH₂CH(OCO₂R³)—CH₂—.

In another aspect, V group is 1-alkene. Oxidation by p450 enzymes isknown to occur at benzylic and allylic carbons.

In yet another aspect of the invention, prodrugs of formula VI are:

wherein

-   -   V is selected from the group consisting of aryl, substituted        aryl, heteroaryl, and substituted heteroaryl, 1-alkenyl, and        1-alkynyl. In another aspect V groups of formula VI are aryl,        substituted, heteroaryl, and substituted heteroaryl. Within such        a group aryl and substituted aryl groups include phenyl and        substituted phenyl. Within such a group heteroaryl groups        include monocyclic substituted and unsubstituted heteroaryl        groups. Such heteroaryls include 4-pyridyl and 3-bromopyridyl.        In another aspect of the invention, Y is —O—.

In one aspect, the compounds of formula I have a group Z which is —H,alkyl, alicyclic, hydroxy, alkoxy,

or —NHCOR. Within such a group are compounds in which Z decreases thepropensity of the byproduct, vinyl aryl ketone to undergo Michaeladditions. Such Z groups are groups that donate electrons to the vinylgroup which is a known strategy for decreasing the propensity ofα,β-unsaturated carbonyl compounds to undergo a Michael addition. Forexample, a methyl group in a similar position on acrylamide results inno mutagenic activity whereas the unsubstituted vinyl analog is highlymutagenic. Other groups could serve a similar function, e.g. Z=OR, NHAc,etc. Other groups may also prevent the Michael addition especiallygroups that result in removal of the double bond altogether such asZ=OH, —OC(O)R, —OCO₂R, and NH₂, which will rapidly undergoretautomerization after the elimination reaction. Certain W and W′groups are also advantageous in this role since the group(s) impede theaddition reaction to the β-carbon or destabilize the product. Anothersuitable Z group is one that contains a nucleophilic group capable ofadding to the α,β-unsaturated double bond after the elimination reactioni.e. (CH₂)_(p)—SH or (CH₂)_(p)—OH where p is 2 or 3. Yet anothersuitable group is a group attached to V which is capable of adding tothe α,β-unsaturated double bond after the elimination reaction:

In another aspect of the invention are prodrugs of formula VII:

-   -   Z² is selected from the group consisting of —CHR²OH, —CHR²OCOR³,        —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, and —CHR²OC(S)OR³.        Within such a group, Z² may be selected from the group of        —CHR²OH, —CHR²OC(O)R³, and —CHR²OCO₂R³. In one aspect of the        invention, Y is —O—.

In another aspect of the invention are prodrugs of formula VIII:

-   -   Z′ is selected from the group consisting of —OH, —OC(O)R³,        —OCO₂R³, and —OC(O)SR³;    -   D′ is —H; and    -   D″ is selected from the group consisting of —H, alkyl, —OR²,        —OH, and —OC(O)R³.

In one aspect of the invention Y is —O—.

In one embodiment, W′ and Z are —H, W and V are both the same aryl,substituted aryl, heteroaryl, or substituted heteroaryl such that thephosphonate prodrug moiety:

has a plane of symmetry. In one aspect of the invention Y is —O—.

In one aspect, oral bioavailability is at least 5%. In another aspect,oral bioavailability is at least 10%.

p450 oxidation can be sensitive to stereochemistry which might either beat phosphorus or at the carbon bearing the aromatic group. The prodrugsof the present invention have two isomeric forms around the phosphorus.One aspect of the invention is the stereochemistry that enables bothoxidation and the elimination reaction. Within such a group are thecompounds where V is trans to the phosphorous-oxygen double bond.

It is envisioned that compounds of formula VIII may utilize a Z′ groupthat is capable of undergoing an oxidative reaction that yields anunstable intermediate which via elimination reactions breaks down to thecorresponding P(O)(O⁻)₂-L-R⁵, P(O)(NHR⁶)₂—R⁵, or P(O)(O⁻)(NHR⁶)-L-R⁵.Within such a group, the Z′ group is OH. Group D″ may be hydrogen,alkyl, and —OR², —OC(O)R³.

With regard to the foregoing aspect of the invention, the inventorscontemplate any combination of the Markush groups as set forth above andthe sub-Markush groups for any variable as described in the followingTables A-Q. TABLE A Table of.Sub-Markush Groups for the Variable R¹ Sub-Markush Group R¹ 1 optionally substituted aryl, optionally substitutedbenzyl, —C(R²)₂OC(O)R³, —C(R²)₂O—C(O)OR³ and —H 2 optionally substitutedaryl, —C(R²)₂OC(O)R³, and —C(R²)₂O—C(O)OR³ 3 aryl and —C(R2)2-aryl 4alkylene-S—S-alkylene-hydroxyl, -alkylene-S—C(O)R³ and -alkylene-S—S—S-alkylenehydroxy or together R¹ and R¹ alkylene-S—S-alkylene to form acyclic group 5 —H 6 —C(R²)₂C(O)OR³ 7 —C(R⁴)₂—C(O)OR³, —C(R²)₂C(O)OR³ 8—C(R²)₂OC(O)R³, —C(R²)₂OC(O)OR³ 9 optionally substituted aryl, 10together R¹ and R¹ are alkyl-S—S-alkyl- to form a cyclic group 11optionally substituted phenyl, —CH₂OC(O)-t-Bu, —CH₂OC(O)OEt,—CH₂OC(O)O-iPr, and H 12 H, optionally substituted aryl, optionallysubstituted alicyclic where the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted -alkylenearyl, —C(R²)₂OC(O)R ,—C(R²)₂—O—C(O)OR³, —C(R²)₂OC(O)SR³, -alkylene-S—C(O)R³, and-alkylene-S—S-alkylenehydroxy 13 H and —(CR¹²R¹³)_(n)—C(O)R¹⁴ 14

15

16

17

18 —(CR¹²R¹³)_(n)—C(O)R¹⁴ 19 R¹ is selected from the group consisting ofphenyl, and phenyl substituted with 1-2 substituents selected from thegroup consisting of —NHC(O)CH₃, —F, —Cl, —Br, —C(O)OCH₂CH₃, and —CH₃ 20R¹ attached to —NR⁶— is —C(R²)₂C(O)OR³, and each R² is independentlyselected from the group consisting of —CH₃, —CH₂CH₃, and —H 21 phenylsubstituted with 1-2 substituents selected from the group of4-NHC(O)CH₃, —Cl, —Br, 2-C(O)OCH₂CH₃ and —CH₃. 22 substituted phenyl 23—CH₂OC(O)OEt 24

TABLE B Table of Sub-Markush Groups for the Variable R⁴ Sub- MarkushGroup R⁴ 1 —H, lower alkyl and lower aryl 2 —H, C1-C4 alkyl 3 H 4substituted phenyl 5 4-hydroxy phenyl 6 together R⁴ and R⁴ are connectedvia 2-5 atoms, optionally including one heteroatom selected from thegroup of O, N and S 7 together R⁴ and R⁴ are connected via 2-5 atoms,optionally including one O

TABLE C Table of Sub-Markush Groups for the Variable R¹² Sub- MarkushGroup R¹² 1 —H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,—CH₂CH₂—SCH₃, phenyl, and benzyl 2 —H, methyl, i-propyl, i-butyl, andbenzyl 3 —H, methyl, i-propyl and benzyl 4 -methyl 5 —H 6 together R¹²and R¹³ are connected via 2-5 carbon atoms to form a cycloalkyl group 7together R¹² and R¹³ are connected via 4 carbon atoms to form acyclopentyl group 8 not the same as R¹³, and R¹⁴—C(O)—CR¹²R¹³—NH₂ is anester or thioester of a naturally occurring amino acid, and R¹⁴ isselected from the group of OR¹⁷ and SR¹⁷

TABLE D Table of Sub-Markush Groups for the Variable R¹³ Sub- MarkushGroup R¹³ 1 —H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,—CH₂CH₂—SCH₃, phenyl, and benzyl 2 —H, methyl, i-propyl, i-butyl, andbenzyl 3 —H, methyl, i-propyl and benzyl 4 methyl, i-propyl and benzyl 5-methyl 6 —H 7 together R¹² and R¹³ are connected via 2-5 carbon atomsto form a cycloalkyl group 8 together R¹² and R¹³ are connected via 4carbon atoms to form a cyclopentyl group 9 not the same as R¹², andR¹⁴—C(O)—CR¹²R¹³—NH₂ is an ester or thioester of a naturally occurringamino acid, and R¹⁴ is selected from the group of OR¹⁷ and SR¹⁷

TABLE E Table of Sub-Markush Groups for the Variable R¹⁵ Sub- MarkushGroup R¹⁵ 1 lower alkyl and lower aralkyl 2 C1-C6 alkyl 3 methyl, ethyland propyl 4 together R¹⁵ and R¹⁶ are connected via 2-6 atoms,optionally including 1 heteroatom selected from the group consisting ofO, N and S 5 together R¹⁵ and R¹⁶ are connected via 2-6 atoms,optionally including 1 heteroatom selected from the group consisting ofO and N

TABLE F Table of Sub-Markush Groups for the Variable R¹⁶ Sub- MarkushGroup R¹⁶ 1 lower alkyl and lower aralkyl 2 C1-C6 alkyl 3 C1-C3 alkyl 4together R¹⁵ and R¹⁶ are connected via 2-6 atoms, optionally including 1heteroatom selected from the group consisting of O, N and S 5 togetherR¹⁵ and R¹⁶ are connected via 2-6 atoms, optionally including 1heteroatom selected from the group consisting of O and N 6 lower alkyl

TABLE G Table of Sub-Markush Groups for the L Variable Sub- MarkushGroup L 1 2,5-furanyl, 2,5-thienyl, 2,6-pyridyl, 2,5-oxazolyl,5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl, 2,4- imidazolyl,2,6-pyrimidinyl, 2,6-pyrazinyl, and 1,3-phenyl 2 2,5-furanyl,2,6-pyridyl, 2,5-oxazolyl, 2,4- imidazolyl, and 1,3-phenyl 32,5-furanyl, methyleneoxycarbonyl, methyleneoxy- methylene, andmethyleneaminocarbonyl 4 2,5-furanyl 5 1,2-ethynyl 6-alkylenecarbonylamino-, -alkyleneaminocarbonyl-, -alkyleneoxycarbonyl-,and -alkyleneoxyalkylene 7 -methylenecarbonylamino-,-methyleneaminocarbonyl-, -methyleneoxycarbonyl-, and-methyleneoxymethylene 8 alkyleneoxyalkylene 9 alkyleneoxycarbonyl 10alkyleneoxyalkylene and alkyleneoxycarbonyl

TABLE H Table of Sub-Markush Groups for the V Variable Sub- MarkushGroup V 1 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl 2 aryl,substituted aryl, heteroaryl, substituted heteroaryl, 1-alkynyl and1-alkenyl 3 aryl, substituted aryl, heteroaryl, and substitutedheteroaryl, 4 aryl and substituted aryl 5 heteroaryl and substitutedheteroaryl 6 optionally substituted monocyclic heteroaryl containing atleast one nitrogen atom 7 phenyl and substituted phenyl 83,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3- chlorophenyl,2-bromophenyl, 3,5-difluorophenyl and 3-bromophenyl, and this group istrans to the phophorusoxygen double bond 9 3,5-dichlorophenyl,3-bromo-4-fluorophenyl, 3- chlorophenyl, 2-bromophenyl,3,5-difluorophenyl, phenyl and 3-bromophenyl 10 3,5-dichlorophenyl,3-bromo-4-fluorophenyl, 3- chlorophenyl, 3,5-difluorophenyl, and3-bromophenyl 11 4-pyridyl 12 —H 13 together V and W are connected viaan additional 3 carbon atoms to form an optionally substituted cyclicgroup containing 6 carbon atoms and substituted with one substituentselected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthio- carbonyloxy, and aryloxycarbonyloxy,attached to one of said additional carbon atoms that is three atoms froma Y attached to the phosphorus 14 together V and W are connected via anadditional 3 carbon atoms to form a cyclic substituted group containing6 carbon atoms and mono-substituted with a substituent selected from thegroup consisting of hydroxyl, acyloxy, alkoxycarbonyloxy, alkylthio-carbonyloxy, and aryloxycarbonyloxy, attached to one of said additionalcarbon atoms that is three atoms from a Y attached to the phosphorus 15together V and W form a cyclic group selected from the group of—CH₂—CH(OH)—CH₂—, —CH₂CH—(OCOR³)—CH₂— and —CH₂CH—(OCO₂R³)—CH₂— 16together V and Z are connected via an additional 3-5 atoms, optionallyincluding 1 heteroatom, to form a cyclic group that is fused to an arylgroup at the beta and gamma position to the Y group 17 together V and Zare connected via an additional 3-5 atoms, optionally including 1heteroatom, to form a cyclic group that is fused to an aryl group at thebeta and gamma position to the Y group, and the aryl group is anoptionally substituted monocyclic aryl group and the connection betweenZ and the aryl group is selected from the group consisting of—O,—CH₂CH₂, —OCH₂ and —CH₂O 18 same aryl, substituted aryl, heteroarylor substituted heteroaryl as W, and V is cis to W 19 optionallysubstituted aryl and optionally substituted heteroaryl

TABLE I Table of Sub-Markush Groups for the Variable V² Sub- MarkushGroup V² 1 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl 2 H, alkyl,alicyclic, aralkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl 3 aryl, substituted aryl, heteroaryl, and substitutedheteroaryl 4 aryl and substituted aryl 5 heteroaryl, substitutedheteroaryl 6 optionally substituted monocyclic heteroaryl containing atleast one nitrogen atom 7 phenyl and substituted phenyl 83,5-dichloro-phenyl, 3-bromo-4-fluorophenyl, 3-chloro- phenyl,3-bromo-phenyl, 2-bromorphenyl and 3,5- difluoro-phenyl 9 4-pyridyl 10together V² and W² are connected via an additional 3 carbon atoms toform an optionally substituted cyclic group containing 6 carbon atomsand substituted with one substituent selected from the group consistingof hydroxy, acyloxy, alkoxycarbonyl-oxy, alkylthio- carbonyloxy, andaryloxy-carbonyloxy, attached to one of said additional carbon atomsthat is three atoms from a Y attached to the phosphorus 11 together V²and W² are connected via an additional 3 carbon atoms to form a cyclicsubstituted group containing 6 carbon atoms and mono-substituted with asubstituent selected from the group consisting of hydroxyl, acyloxy,alkoxycarbonyl-oxy, alkylthio- carbonyloxy, and aryloxy-carbonyloxy,attached to one of said additional carbon atoms that is three atoms froma Y attached to the phosphorus 12 together V² and W² form a cyclic groupselected from the group of —CH₂—CH(OH)—CH₂—, —CH₂CH—(OCOR³)—CH₂— and—CH₂CH—(OCO₂R³)—CH₂— 13 together V² and Z² are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 ring atoms,optionally containing 1 heteroatom, and substituted with hydroxy,acylocy, alkoxy carbonyloxy, oraryloxycarbon yloxy attached to a carbnatom that is three atoms from a Y attached to phosphorus 14 —H

TABLE J Table of Sub-Markush Groups for the W Variable Sub- MarkushGroup W 1 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl 2 —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl 3 —H, —R³, aryl, substituted aryl, heteroaryl,and substituted heteroaryl 4 aryl, substituted aryl, heteroaryl andsubstituted heteroaryl 5 same as W′ 6 —H 7 together V and W areconnected via an additional 3 carbon atoms to form an optionallysubstituted cyclic group containing 6 carbon atoms and substituted withone substituent selected from the group consisting of hydroxy, acyloxy,alkoxy- carbonyloxy, alkylthio-carbonyloxy, and aryloxy- carbonyloxy,attached to one of said additional carbon atoms that is three atoms froma Y attached to the phosphorus 8 together V and W are connected via anadditional 3 carbon atoms to form a cyclic substituted group containing6 carbon atoms and mono-substituted with a substituent selected from thegroup consisting of hydroxyl, acyloxy, alkoxycarbonyl- oxy,alkylthio-carbonyloxy, and aryloxy- carbonyloxy, attached to one of saidadditional carbon atoms that is three atoms from a Y attached to thephosphorus 9 together V and W form a cyclic group selected from thegroup of —CH₂—CH(OH)—CH₂—, —CH₂CH—(OCOR³)CH₂—, and —CH₂CH—(OCO₂R³)—CH₂—10 together V and W form a cyclic group selected from the group of—CH₂—CH(OH)-CH₂—, —CH₂CH—(OCOR³)—CH₂— and —CH₂CH—(OCO₂R³)—CH₂— 11together W and W′ are connected via an additional 2-5 atoms to form acyclic group, optionally containing 0-2 heteroatoms, and V is aryl,substituted aryl heteroaryl or substituted heteroaryl 12 same aryl,substituted aryl, heteroaryl or substituted heteroaryl as V, and W iscis to V

TABLE K Table of Sub-Markush Groups for the W′ Variable Sub- MarkushGroup W′ 1 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl 2 —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl 3 —H, —R³, aryl, substituted aryl, heteroaryl,and substituted heteroaryl 4 same as W 5 —H 6 together W and W′ areconnected via an additional 2-5 atoms to form a cyclic group, optionallycontaining 0-2 heteroatoms, and V is aryl, substituted aryl, heteroarylor substituted heteroaryl

TABLE L Table of Sub-Markush Groups for the W² Variable Sub- MarkushGroup W² 1 —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl 2 —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl 3 —H, —R³, aryl, substituted aryl, heteroaryl,and substituted heteroaryl 4 aryl, substituted aryl, heteroaryl andsubstituted heteroaryl 5 same as W″ 6 —H 7 together V² and W² areconnected via an additional 3 carbon atoms to form an optionallysubstituted cyclic group containing 6 carbon atoms and substituted withone substituent selected from the group consisting of hydroxy, acyloxy,alkoxy- carbonyloxy, alkylthio-carbonyloxy, and aryloxy-carbonyloxy,attached to one of said additional carbon atoms that is three atoms froma Y attached to the phosphorus 8 together V² and W² are connected via anadditional 3 carbon atoms to form a cyclic substituted group containing6 carbon atoms and mono-substituted with a substituent selected from thegroup consisting of hydroxyl, acyloxy, alkoxycarbonyl-oxy,alkylthio-carbonyloxy, and aryloxy-carbonyloxy, attached to one of saidadditional carbon atoms that is three atoms from a Y attached to thephosphorus 9 together V² and W² form a cyclic group selected from thegroup of —CH₂—CH(OH)—CH₂—, —CH₂CH—(OCOR³)CH₂—, and —CH₂CH—(OCO₂R³)—CH₂—10 together V² and W² form a cyclic group selected from the group of—CH₂—CH(OH)—CH₂—, —CH₂CH—(OCOR³)—CH₂— and —CH₂CH—(OCO₂R³)—CH₂—

TABLE M Table of Sub-Markush Groups for the Y Variable Sub- MarkushGroup Y 1 both Y groups are —O— 2 both Y groups are —NR⁶— 3 Y is —O—located adjacent to the W′, W, W″, and W² groups 4 Y is —O— locatedadjacent to the V group or V² group 5 one Y is —NR⁶—, and one Y is —O— 6one Y is —NR⁶—, and the other YR¹ is —NR¹⁵R¹⁶, —OR⁷ orNR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴ 7 one Y is —NR⁶—, and the other YR¹ is—NR¹⁵R¹⁶, and R¹⁵ is not H 8 one Y is —NR⁶—, and the other YR¹ is—NR¹⁵R¹⁶, and R¹⁶ is —(CR¹²R¹³)_(n)—C(O)—R¹⁴ 9 both Y groups are thesame —NR⁶—, such that the phosphonate prodrug moiety has a plane of sym-metry through the phosphorus-oxygen double bond 10 one Y is —NR⁶—, andthe other YR¹ is —NR¹⁵R¹⁶, where —NR¹⁵R¹⁶is a cyclic amine 11 one Y is—NR⁶—, and the other YR¹ is —NR¹⁵R¹⁶, where —NR¹⁵R¹⁶ is selected fromthe group consisting of morpholinyl and pyrrolidinyl 12 one Y is —NR⁶—,and the other YR¹ is —NR¹⁵R¹⁶, where —NR¹⁵R¹⁶ is —(CR¹²R¹³)_(n)—C(O)R¹⁴

TABLE N Table of Sub-Markush Groups for the Z Variable Sub- MarkushGroup Z 1 —OR², —SR², —R², —NR² ₂, —OC(O)R³, —OCO₂R³, —SC(O)R³, —SCO₂R³,—NHC(O)R², —NHCO₂R³, —(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹ 2 —OR², —R²,—OC(O)R³, —OCO₂R³, —NHC(O)R², —NHCO₂R³, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹ 3 —OR², —H, —OC(O)R³, —OCO₂R³, and —NHC(O)R² 4 —CHR²OH,—CHR²O—C(O)R³, and —CHR²O—CO₂R³ 5 —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³,—CHR²OC(S)OR³, —CHR²OC(O)SR³, —CHR²OCO₂R³, —OR², —SR², —CHR², —CHR²N₃,—CH₂aryl, —CH(aryl)OH, CH(CH═CR² ₂)OH CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³,—OCO₂R³, —SCOR³, —SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)p-OR¹⁹and —(CH₂)p-SR¹⁹ 6 —OR², —SR², —CHR²N₃, —R², —OC(O)R², —OCO₂R³,—SC(O)R³,—SCO₂R³, —NHC(O)R², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹ 7 —OR², —R², —OC(O)R³,—OCO₂R³, —CH₃, —NHC(O)R²,—NHCO₂R³, —(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹ 8 —H, OR², and —NHC(O)R²9 —H 10 together V and Z are connected via an additional 3-5 atoms,optionally including 1 heteroatom, to form a cyclic group that is fusedto an aryl group at the beta and gamma position to the Y group 11together Z and W are connected via an additional 3-5 atoms to form acyclic group, optionally containing one heteroatom, and V is aryl,substituted aryl, heteroaryl or substituted heteroaryl

TABLE O Table of Sub-Markush Groups for the Z′ Variable Sub- MarkushGroup Z′ 1 —OR², —SR², —R², —NR² ₂, —OC(O)R³, —OCO₂R³, —SC(O)R³,—SCO₂R³, —NHC(O)R², —NHCO₂R³, —(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹ 2—OR², —R², —OC(O)R³, —OCO₂R³, —NHC(O)R², —NHCO₂R³, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹ 3 —OR², —H, —OC(O)R³, —OCO₂R³, and —NHC(O)R²v 4 —CHR²OH,—CHR²O—C(O)R³, and —CHR²O—CO₂R³ 5 —OH, —OC(O)R³, —OCO₂R³ and —OC(O)SR³ 6—OH, —OC(O)R³, and —OCO₂R³ 7 —OR², —SR², —CHR²N₃, —R², —OC(O)R²,—OCO₂R³, —SC(O)R³, —SCO₂R³, —NHC(O)R², —NHCO₂R³, —CH₂NHaryl,—(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹ 8 —OR², —R², —OC(O)R², —OCO₂R³,—CH₃, —NHC(O)R², —NHCO₂R³, —(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹ 9 —H,OR², and —NHC(O)R² 10 —H

TABLE P Table of Sub-Markush Groups for the Z² Variable Sub- MarkushGroup Z² 1 —OR², —SR², —R², —NR² ₂, —OC(O)R³, —OCO₂R³, —SC(O)R³,—SCO₂R³, —NHC(O)R², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹ 2 —OR², —R², —OC(O)R³, —OCO₂R³, —NHC(O)R², —NHCO₂R³,—(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹ 3 —OR², —H, —OC(O)R³, —OCO₂R³, and—NHC(O)R² 4 —CHR²OH, —CHR²O—C(O)R³, and —CHR²O—CO₂R³ 5 —CHR²OH,—CHR²OC(O)R³, —CHR²OC(S)R³, CHR²OCO₂R³, —CHR²OC(O)SR³,—CHR²OC(S)OR³,—CH(aryl)OH, CH(CH═CR² ₂)OH, CH(C≡CR²)OH, —SR², —CH₂NHaryl, —CH₂aryl 6—CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, CHR²OCO₂R³, —CHR²OC(O)SR³,—CHR²OC(S)OR³, —CH₂aryl 7 —OR², —SR², —CHR²N₃, —R², —OC(O)R², —OCO₂R³,—SC(O)R³, —SCO₂R³, —NHC(O)R², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹ 8 —OR², —R², —OC(O)R², —OCO₂R³, —CH₃, —NHC(O)R²,—NHCO₂R³, —(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹ 9 —H, OR², and —NHC(O)R²10 —H 11 together V² and Z² are connected via an additional 3-5 atoms toform a cyclic group containing 5-7 ring atoms, optionally containing 1heteroatom, and substituted with hydroxy, acylocy, alkoxy carbonyloxy,oraryloxycarbon yloxy attached to a carbn atom that is three atoms froma Y attached to phosphorus

TABLE Q Table of Markush Groups by Variable Markush Markush MarkushMarkush Markush Group A Group B Group C Group D Group E n 1 and 2 1 2 1,and the carbon attached to R¹² and R¹³ has S stereo- chemistry p 2 3 R²—H, lower alkyl, ethyl, methyl —H, and aryl —H lower aryl, lower and Halicyclic, and lower aralkyl R³ lower alkyl, lower alkyl, ethyl andlower aryl, lower lower aryl methyl alicyclic and lower aralkyl R⁵substituted substituted substituted substituted substituted phenyl,pyrrolyl, pyrrolyl, thienyl, phenyl substituted substituted substitutedsubstituted pyrrolyl, oxazolyl, oxazolyl, furanyl substitutedsubstituted substituted and oxazolyl, thiazolyl, thiazolyl, substitutedsubstituted substituted substituted phenyl thiazolyl, isothiazolyl,isothiazolyl, substituted substituted substituted isothiazolyl,pyrazolyl, pyrazolyl, substituted substituted substituted pyrazolyl,isoxazolyl, isoxazolyl, substituted substituted substituted isoxazolyl,pyridinyl, pyridinyl, substituted substituted substituted pyridinyl,thienyl, pyrimidinyl, substituted substituted and thienyl, furanyl,substituted substituted substituted pyridazinyl furanyl, pyrimidinyl,substituted and pyrimidinyl, and substituted substituted pyridazinylpyridazinyl R⁶ —H, and lower —H and C1-C6 —H, methyl, —H and —H alkyl,alkyl and ethyl methyl acyloxyalkyl R⁷ lower alkyl, lower alkyl andlower aryl substituted phenyl, phenyl lower aryl and lower aryl phenylsubstituted with lower alicyclic 4—NHC(O)CH₃, —Cl, —Br, 2— C(O)OCH₂CH₃,or —CH₃ R¹¹ alkyl and aryl lower alkyl C1-C4 alkyl methyl R¹⁴ OR¹⁷, SR¹⁷and OR¹⁷ and SR¹⁷ OR¹⁷ NR²R²⁰ R¹⁷ lower alkyl, methyl, ethyl, methyl,ethyl and lower aryl, lower isopropyl, ethyl, isopropyl aralkyl,alicyclic, propyl, t-butyl, isopropyl, or together R¹⁷ and benzyl propyland and R¹⁷ are benzyl connected via 2-6 atoms optionally including 1heteroatom selected from the group of N, O, and S R¹⁸ —H and lower —H,methyl and alkyl ethyl R¹⁹ —H and acetyl —H R²⁰ —H, C1-C4 alkyl, —H andC1-C4 C4-C6 aryl, C2-C7 alkyl alicyclic and C5-C7 aralkyl D″ —H, alkyl,—H OH, and —OC(O)R³ G² C and O C O G³ C and S C S G⁴ C and N C N J² —H,—NR⁴ ₂, —H, —NO₂, lower —OCH₃, —CN, —OCH₃ —H, —OR³, —NO₂, —C(O)NR⁴ ₂,alkyl, lower —H, halo, halo, —(CH₂)₂aryl, —CO₂R³, halo, alkylaryl, lower—NH₂ and —(CH₂)₂NHaryl, —S(O)₂NHR⁷, —S(O)₂NR⁴ ₂, alkoxy, lower —NO₂ —CN,—NR⁴ ₂ lower alkyl, perhaloalkyl, lower alicyclic, halo, —CH₂NHR⁴, loweralkenyl, —C(O)NR⁴ ₂, lower alkynyl, —S(O)₂NHR⁴, lower perhalo- —OH,—NH₂, and alkyl, lower —NHC(O)R² haloalkyl, lower aryl, lower alkylaryl,lower alkylene—OH, —OR¹¹, —CR² ₂NR⁴ ₂, —CN, —C(S)NR⁴ ₂, —OR², —SR², —N₃,—NO₂, —NHC(S)NR⁴ ₂, —NR¹⁸C(O)R², and —CR² ₂CN J³ —H, —NR⁴ ₂, —H, —NO₂,lower —OCH₃, not halo or —H, —OR³, —NO₂, —C(O)NR⁴ ₂, alkyl, lower —CN,alkenyl halo,—(CH₂)₂aryl, —CO₂R³, halo, alkylaryl, lower —H, halo,—(CH₂)₂NHaryl, —S(O)₂NR⁴ ₂, alkoxy, lower —NH₂ and —S(O)₂NHR⁷, loweralkyl, perhaloalkyl, —NO₂ —CN, —NR⁴ ₂ lower alicyclic, halo, —CH₂NHR⁴,lower alkenyl, —C(O)NR⁴ ₂, lower alkynyl, —S(O)₂NHR⁴, lower perhalo-—OH, —NH₂, and alkyl, lower —NHC(O)R² haloalkyl, lower aryl, loweralkylaryl, lower alkylene—OH, —OR¹¹, —CR² ₂NR⁴ ₂, —CN,—C(S)NR⁴ ₂, —OR²,—SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, —NR¹⁸C(O)R², and —CR² ₂CN J⁴ —H, —NR⁴ ₂,—H, —NO₂, lower —OCH₃, not halo or —H, —OR³, —NO₂, —C(O)NR⁴ ₂, alkyl,lower —CN, alkenyl halo, —(CH₂)₂aryl, —CO₂R³, halo, alkylaryl, lower —H,halo, —(CH₂)₂NHaryl, —S(O)₂NR⁴ ₂, alkoxy, lower —NH₂ and —S(O)₂NHR⁷,lower alkyl, perhaloalkyl, —NO₂ —CN, —NR⁴ ₂ lower alkenyl, halo,—CH₂NHR⁴, lower alkenyl, —C(O)NR⁴ ₂, lower alkynyl, —S(O)₂NHR⁴, lowerperhalo- —OH, —NH₂, and alkyl, lower —NHC(O)R² haloalkyl, lower aryl,lower alkylaryl, lower alkylene—OH, —OR¹¹, —CR² ₂NR⁴2, —CN, —C(S)NR⁴ ₂,—OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, —NR¹⁸C(O)R², and —CR² ₂CN J⁵ —H,—NR⁴ ₂, —H, —NO₂, lower —OCH₃, —CN, not halo or —H, —OR³, —NO₂, —C(O)NR⁴₂, alkyl, lower —H, halo, alkenyl halo, —(CH₂)₂aryl, —CO₂R³, halo,alkylaryl, lower —NO₂ and —(CH₂)₂NHaryl, —S(O)₂NR⁴ ₂, alkoxy, lower—CH₂NHR⁴ —S(O)₂NHR⁷, lower alkyl, perhaloalkyl, —CN, —NR⁴ ₂ loweralenyl, halo, —CH₂NHR⁴, lower alkenyl, —C(O)NR⁴ ₂, lower alkynyl,—S(O)₂NHR⁴, lower perhalo- —OH, —NH₂, and alkyl, lower —NHC(O)R²haloalkyl, lower aryl, lower alkylaryl, lower alkylene—OH, —OR¹¹, —CR²₂NR⁴ ₂, —CN, —C(S)NR⁴ ₂, —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂,—NR¹⁸C(O)R², and —CR² ₂CN J⁶ —H, —NR⁴ ₂, —H, —NO₂, lower —OCH₃, —C(O)NR⁴₂, alkyl, lower aryl, —CN —CO₂R³, halo, lower alkylaryl, —H, halo,—S(O)₂NR⁴ ₂, lower alkoxy, and lower lower alkyl, lower alkyl loweralkenyl, perhaloalkyl, lower alkenyl, halo, —CH₂NHR⁴, lower alkynyl,—C(O)NR⁴ ₂, lower perhalo- —S(O)₂NHR⁴, alkyl, lower —OH, —NH₂, andhaloalkyl, lower —NHC(O)R² aryl, lower alkylaryl, lower alkylene—OH,—OR¹¹, —CR² ₂NR⁴ ₂, —CN, —C(S)NR⁴ ₂, —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴₂, —NR¹⁸C(O)R², and —CR² ₂CN W³ —H, alkyl —H W″ —H, alkyl, —H, —R³,aryl, —H, alkyl, same as —H aralkyl, substituted aryl, aralkyl, W²alicyclic, aryl, heteroaryl, and alicyclic, substituted substitutedaryl, aryl, heteroaryl, heteroaryl substituted substituted aryl,heteroaryl, heteroaryl, 1-alkenyl, and substituted 1-alkynyl heteroarylX³ C N X⁴ C N X⁵ C N

In the following examples of compounds, the following prodrugs areenvisioned:

-   Acyloxyalkyl esters;-   Alkoxycarbonyloxyalkyl esters;-   Aryl esters;-   Benzyl and substituted benzyl esters;-   Disulfide containing esters;-   Substituted (1,3-dioxolen-2-one)methyl esters;-   Substituted 3-phthalidyl esters;-   Cyclic-[5-hydroxycyclohexan-1,3-diyl) diesters and hydroxy protected    forms;-   Cyclic-[2-hydroxymethylpropan-1,3-diyl]diesters and hydroxy    protected forms;-   Cyclic-(1-arylpropan-1,3-diyl);-   Monoaryl ester N-substituted mono phosphoramidates;-   Bis Omega substituted lactone esters; and all mixed esters resulted    from possible combinations of above esters;

Also envisioned are the following:

-   Bis-pivaloyloxymethyl esters;-   Bis-isobutyryloxymethyl esters;-   Cyclic-[1-(3-chlorophenyl)propan-1,3-diyl]diesters;-   Cyclic-[1-(3,5-dichlorophenyl)propan-1,3-diyl]diester;-   Cyclic-[1-(3-bromo-4-fluorophenyl)propan-1,3-diyl]diester;-   Cyclic-[2-hydroxymethylpropan-1,3-diyl]diester;-   Cyclic-[2-acetoxymethylpropan-1,3-diyl]diester;-   Cyclic-[2-methyloxycarbonyloxymethylpropan-1,3-diyl]diester;-   Cyclic-[1-phenylpropan-1,3-diyl]diesters;-   Cyclic-[1-(2-pyridyl)propan-1,3-diyl)]diesters;-   Cyclic-[1-(3-pyridyl)propan-1,3-diyl]diesters;-   Cyclic-[1-(4-pyridyl)propan-1,3-diyl]diesters;-   Cyclic-[5-hydroxycyclohexan-1,3-diyl]diesters and hydroxy protected    forms;-   Bis-benzoylthiomethyl esters;-   Bis-benzoylthioethyl esters;-   Bis-benzoyloxymethyl esters;-   Bis-p-fluorobenzoyloxymethyl esters;-   Bis-6-chloronicotinoyloxymethyl esters;-   Bis-5-bromonicotinoyloxymethyl esters;-   Bis-thiophenecarbonyloxymethyl esters;-   Bis-2-furoyloxymethyl esters;-   Bis-3-furoyloxymethyl esters;-   Diphenyl esters;-   Bis-(4-methoxyphenyl)esters;-   Bis-(2-methoxyphenyl)esters;-   Bis-(2-ethoxyphenyl)esters;-   Mono-(2-ethoxyphenyl)esters;-   Bis-(4-acetamidophenyl)esters;-   Bis-(4-acetoxyphenyl)esters;-   Bis-(4-hydroxyphenyl)esters;-   Bis-(2-acetoxyphenyl)esters;-   Bis-(3-acetoxyphenyl)esters;-   Bis-(4-morpholinophenyl)esters;-   Bis-[4-(1-triazolophenyl)esters;-   Bis-(3-N,N-dimethylaminophenyl)esters;-   Bis-(1,2,3,4-tetrahydronapthalen-2-yl)esters;-   Bis-(3-chloro-4-methoxy)benzyl esters;-   Bis-(3-bromo-4-methoxy)benzyl esters;-   Bis-(3-cyano-4-methoxy)benzyl esters;-   Bis-(3-chloro-4-acetoxy)benzyl esters;-   Bis-(3-bromo-4-acetoxy)benzyl esters;-   Bis-(3-cyano-4-acetoxy)benzyl esters;-   Bis-(4-chloro)benzyl esters;-   Bis-(4-acetoxy)benzyl esters;-   Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters;-   Bis-(3-methyl-4-acetoxy)benzyl esters;-   Bis-(benzyl)esters;-   Bis-(3-methoxy-4-acetoxy)benzyl esters;-   Bis-(6′-hydroxy-3′,4′-dithia)hexyl esters;-   Bis-(6′-acetoxy-3′,4′-dithia)hexyl esters;-   (3,4-dithiahexan-1,6-diyl)esters;-   Bis-(5-methyl-1,3-dioxolen-2-one-4-yl)methyl esters;-   Bis-(5-ethyl-1,3-dioxolen-2-one-4-yl)methyl esters;-   Bis-(5-tert-butyl-1,3-dioxolen-2-one-4-yl)methyl esters;-   Bis-3-(5,6,7-trimethoxy)phthalidyl esters;-   Bis-(cyclohexyloxycarbonyloxymethyl)esters;-   Bis-(isopropyloxycarbonyloxymethyl)esters;-   Bis-(ethyloxycarbonyloxymethyl)esters;-   Bis-(methyloxycarbonyloxymethyl)esters;-   Bis-(isopropylthiocarbonyloxymethyl)esters;-   Bis-(phenyloxycarbonyloxymethyl)esters;-   Bis-(benzyloxycarbonyloxymethyl)esters;-   Bis-(phenylthiocarbonyloxymethyl)esters;-   Bis-(p-methoxyphenoxycarbonyloxymethyl)esters;-   Bis-(m-methoxyphenoxycarbonyloxymethyl)esters;-   Bis-(o-methoxyphenoxycarbonyloxymethyl)esters;-   Bis-(o-methylphenoxycarbonyloxymethyl)esters;-   Bis-(p-chlorophenoxycarbonyloxymethyl)esters;-   Bis-(1,4-biphenoxycarbonyloxymethyl)esters;-   Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;-   Bis-(N-phenyl-N-methylcarbamoyloxymethyl)esters;-   Bis-(2,2,2-trichloroethyl)esters;-   Bis-(2-bromoethyl)esters;-   Bis-(2-iodoethyl)esters;-   Bis-(2-azidoethyl)esters;-   Bis-(2-acetoxyethyl)esters;-   Bis-(2-aminoethyl)esters;-   Bis-(2-N,N-dimethylaminoethyl)esters;-   Bis-(2-aminoethyl)esters;-   Bis-(methoxycarbonylmethyl)esters;-   Bis-(2-aminoethyl)esters;-   Bis-[N,N-di(2-hydroxyethyl)]carbamoylmethylesters;-   Bis-(2-aminoethyl)esters;-   Bis-(2-methyl-5-thiazolomethyl)esters;-   Bis-(bis-2-hydroxyethylcarbamoylmethyl)esters.-   O-(3,4-methylenedioxyphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(O-Phenyl-3,4-methylenedioxy)(-N(H)CH(Me)CO₂Et)-   O-(3,4-methylenedioxyphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(O-Phenyl-3,4-methylenedioxy)(-NH—C(CH₃)₂—CO₂Et)-   O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh)(N(H)—CH(Me)CO₂Et)-   O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh)(N(H)—CH(Me)CO₂Me)-   O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-3-Cl)(NH—CH(Me)CO₂Et)-   O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-2-Cl)(NH—CH(Me)CO₂Et)-   O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-4-Cl)(NH—CH(Me)CO₂Et)-   O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-4-NHAc)(NH—CH(Me)CO₂Et)-   O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-2-CO₂Et)(NH—CH(Me)CO₂Et)-   O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh)(NH—C(Me)₂CO₂Et)-   O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh)(NH—C(Me)₂CO₂Me)-   O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-3-Cl)(NH—C(Me)₂CO₂Et)-   O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-2-Cl)(NH—C(Me)₂CO₂Et)-   O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-4-Cl)(NH—C(Me)₂CO₂Et)-   O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-4-NHAc)(NH—C(Me)₂CO₂Et)-   O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-2-CO₂Et)(NH—C(Me)₂CO₂Et)-   O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh)(NH—CH₂CO₂Et)-   O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh)(NH—CH₂CO₂Me)-   O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-3-Cl)(NH—CH₂CO₂Et)-   O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-2-Cl)(NH—CH₂CO₂Et)-   O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-4-Cl)(NH—CH₂CO₂Et)-   O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-4-NHAc)(NH—CH₂CO₂Et)-   O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-2-CO₂Et)(NH—CH₂CO₂Et)

Further envisioned are the following:

-   Bis-pivaloyloxymethyl esters;-   Bis-isobutyryloxymethyl esters;-   Cyclic-[1-(3-chlorophenyl)propan-1,3-diyl]diesters;-   Cyclic-[1-3,5-dichlorophenyl)propan-1,3-diyl]diester;-   Cyclic-[1-(3-bromo-4-fluorophenyl)propan-1,3-diyl]diester;-   Cyclic-(2-hydroxymethylpropan-1,3-diyl)ester;-   Cyclic-(2-acetoxymethylpropan-1,3-diyl)ester;-   Cyclic-(2-methyloxycarbonyloxymethylpropan-1,3-diyl)ester;-   Cyclic-(2-cyclohexylcarbonyloxymethylpropan-1,3-diyl)ester;-   Cyclic-[phenylpropan-1,3-diyl]diesters;-   Cyclic-[1-(2-pyridyl)propan-1,3-diyl)]diesters;-   Cyclic-[1-(3-pyridyl)propan-1,3-diyl]diesters;-   Cyclic-[1-(4-pyridyl)propan-1,3-diyl]diesters;-   Cyclic-[5-hydroxycyclohexan-1,3-diyl]diesters and hydroxy protected    forms;-   Bis-benzoylthiomethyl esters;-   Bis-benzoylthioethylesters;-   Bis-benzoyloxymethyl esters;-   Bis-p-fluorobenzoyloxymethyl esters;-   Bis-6-chloronicotinoyloxymethyl esters;-   Bis-5-bromonicotinoyloxymethyl esters;-   Bis-thiophenecarbonyloxymethyl esters;-   Bis-2-furoyloxymethyl esters;-   Bis-3-furoyloxymethyl esters;-   Diphenyl esters;-   Bis-(2-methylphenyl)esters;-   Bis-(2-methoxyphenyl)esters;-   Bis-(2-ethoxyphenyl)esters;-   Bis-(4-methoxyphenyl)esters;-   Bis-(3-bromo-4-methoxybenzyl)esters;-   Bis-(4-acetoxybenzyl)esters;-   Bis-(3,5-dimethoxy-4-acetoxybenzyl)esters;-   Bis-(3-methyl-4-acetoxybenzyl)esters;-   Bis-(3-methoxy-4-acetoxybenzyl)esters;-   Bis-(3-chloro-4-acetoxybenzyl)esters;-   Bis-(cyclohexyloxycarbonyloxymethyl)esters;-   Bis-(isopropyloxycarbonyloxymethyl)esters;-   Bis-(ethyloxycarbonyloxymethyl)esters;-   Bis-(methyloxycarbonyloxymethyl)esters;-   Bis-(isopropylthiocarbonyloxymethyl)esters;-   Bis-(phenyloxycarbonyloxymethyl)esters;-   Bis-(benzyloxycarbonyloxymethyl)esters;-   Bis-(phenylthiocarbonyloxymethyl)esters;-   Bis-(p-methoxyphenoxycarbonyloxymethyl)esters;-   Bis-(m-methoxyphenoxycarbonyloxymethyl)esters;-   Bis-(o-methoxyphenoxycarbonyloxymethyl)esters;-   Bis-(o-methylphenoxycarbonyloxymethyl)esters;-   Bis-(p-chlorophenoxycarbonyloxymethyl)esters;-   Bis-(1,4-biphenoxycarbonyloxymethyl)esters;-   Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;-   Bis-(6-hydroxy-3,4-dithia)hexyl esters;-   Cyclic-(3,4-dithiahexan-1,6-diyl)esters;-   Bis-(2-bromoethyl)esters;-   Bis-(2-aminoethyl)esters;-   Bis-(2-N,N-diaminoethyl)esters;-   O-(3,4-methylenedioxyphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(O-Phenyl-3,4-methylenedioxy)(-N(H)CH(Me)CO₂Et)-   O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh)(NH—*CH(Me)CO₂Et)-   O-(3,4-methylenedioxyphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(O-Phenyl-3,4-methylenedioxy)(-NH—C(CH₃)₂—CO₂Et)-   O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh)(NH—*CH(Me)CO₂Me)-   O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-3-Cl)(NH—*CH(Me)CO₂Et)-   O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-2-Cl)(NH—*CH(Me)CO₂Et)-   O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-4-Cl)(NH—*CH(Me)CO₂Et)-   O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-4-NHAc)(NH—*CH(Me)CO₂Et)-   O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates(-P(O)(OPh-2-CO₂Et)(NH—*CH(Me)CO₂Et)-   O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh)(NH—C(Me)₂CO₂Et)-   O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh)(NH—C(Me)₂CO₂Me)-   O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-3-Cl)(NH—C(Me)₂CO₂Et)-   O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-2-Cl)(NH—C(Me)₂CO₂Et)-   O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-4-Cl)(NH—C(Me)₂CO₂Et)-   O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates(-P(O)(OPh-4-NHAc)(NH—C(Me)₂CO₂Et)-   O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates    (-P(O)(OPh-2-CO₂Et)(NH—C(Me)₂CO₂Et)    In the above prodrugs an asterisk (*) on a carbon refers to the    L-configuration.-   O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh)(NH—CH₂CO₂Et)-   O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh)(NH—CH₂CO₂Me)-   O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-3-Cl)(NH—CH₂CO₂Et)-   O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-2-Cl)(NH—CH₂CO₂Et)-   O-(4-chlorophenyl)-N-(ethoxycarbonyl)methyl]phosphoramidates-(-O(O)OPh-4-Cl)(NH—CH₂CO₂Et)-   O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-4-NHAc)(NH—CH₂CO₂Et)-   O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(-P(O)(OPh-2-CO₂Et)(NH—CH₂CO₂Et).

Examples of compounds of formula I include, but are not limited topharmaceutically acceptable salts and prodrugs of the,compounds named inTables 1 and 2 as follows: TABLE 1

Table 1 cmpd M-1 HPLC no. L X³ X⁴ X⁵ J² J³ J⁴ J⁵ J⁶ found Rt 1.01 L1 C CC H NO₂ H NO₂ H 313 5.30′ 1.02 L1 C C C NH₂ NO₂ H NO₂ H 328 5.58′ 1.03L1 C C C MeO H H Cl H 287 5.71′ 1.04 L1 C C C Cl H H Cl H 291/293 6.27′1.05 L1 C C C SO₂NHMe H H CF₃ H 384 5.82′ 1.06 L1 C C C SO₂NHMe H H Cl H350 5.43′ 1.07 L1 C C C SO₂NHMe H H H H 316 5.25′ 1.08 L1 C C CSO₂NH(n-Pr) H H H H 378 6.12′ 1.09 L1 C C C OH H H H H 239 3.97′ 1.10 L1C C C H Me H Me H 251 6.10′ 1.11 L1 C C C H Br H H H 301/303 5.90′ 1.12L1 C C C H H NH₂ H H 238 4.64′ 1.13 L1 C C C MeO H Cl MeO H 317 6.00′1.14 L1 C C C C(O)NHCH₂- H H H H 390 6.12′ (4-ClPh) 1.15 L1 C C CC(O)NHCH₂— H H H H 404 6.42′ CH₂(4- ClPh) 1.16 L1 C C C SO₂NHBn H H H H392 6.17′ 1.17 L1 C C C SO₂NH₂ H H H H 302 4.44′ 1.18 L1 C C C Me Me MeMe Me 293 5.08′ 1.19 L1 C C C CO₂Et CO₂Et H H H 367 6.00′ 1.20 L1 C C CH Me NHAc H H 294 4.12′ 1.21 L1 C C C Cl H Cl H Me 305/307 6.66′ 1.22 L1C C C CO₂Me H OH H H 297 4.71′ 1.23 L1 C C C C(O)NH₂ H Me H H 280 6.89′1.24 L1 C C C CO₂Et H OH H H 311 5.56′ 1.25 L1 C C C H H NO₂ H H 2684.81′ 1.26 L1 C C C C(O)NH(2,4- H H H H 378 5.56′ difluoro-Ph) 1.27 L1 CC C H Cl H Cl H 291/293 6.43′ 1.28 L1 C C C H OH H H H 239 4.41′ 1.29 L1C C C H CO₂H H Br H 345/347 5.37′ 1.30 L1 C C C MeO MeO H CHO H 31.15.12′ 1.31 L1 C C C NO₂ H H H H 268 4.78′ 1.32 L1 C C C Ph H H H H 2996.75′ 1.33 L1 C C C CO₂Et H H H H 295 5.32′ 1.34 L1 C C C H H Br H H301/303 6.01 1.35 L1 C C C H C(O)Et H H H 279 4.54′ 1.36 L1 C C C MeO HH CN H 278 5.18′ 1.37 L1 C C C Et H H H H 251 5.13′ 1.38 L1 C C C NO₂ HH H Me 282 5.76′ 1.39 L1 C C C H H NHAc H H 280 3.94′ 1.40 L1 C C C MeMe Me Me H 279 7.07′ 1.41 L1 C C C H Ph H H H 299 7.02′ 1.42 L1 C C CSO₂NH₂ H H Cl H 336 5.37′ 1.43 L1 C C C H H NHC(O)— H H 349 5.06′ CH₂-(pyrrolidin- 1-yl) 1.44 L1 C C C H Me Me H H 251 5.10′ 1.45 L1 C C C NO₂H NO₂ H H 313 5.59′ 1.46 L1 C C C H CH₂NH₂ H H H 252 2.35′ 1.47 L1 C C CH F NH₂ H H 256 5.08′ 1.48 L1 C C C H CH2OH H H H 253 4.52′ 1.49 L1 C CC Br H H H H 301/303 5.72′ 1.50 L1 C C C CH₂CH₂OH H H H H 267 5.51′ 1.51L1 C C C H H C(O)NH₂ H H 266 3.61′ 1.52 L1 C C C H H CN H H 248 3.64′1.53 L1 C C C H CN H H H 248 3.98′ 1.54 L1 C C C CN H H H H 248 4.96′1.55 L1 C C C H NO₂ NH₂ H H 283 5.01′ 1.56 L1 C C C i-Pr H H H H 2656.86′ 1.57 L1 N C C Cl null NH₂ H H 273 3.98′ 1.59 L1 C C C NH₂ H H Cl H272 5.44′ 1.60 L1 C C C H CI H F H 275 5.08′ 1.61 L1 C C C MeO H H CN H278 5.44′ 1.62 L1 C C C Me H H NO₂ H 282 5.88′ 1.63 L1 C C C H NO₂ H F H286 4.68′ 1.64 L1 C C C NH₂ H H CO₂Me H 296 5.18′ 1.65 L1 C C C MeO H HNO₂ H 298 5.52′ 1.66 L1 C C C Cl H H CF₃ H 325 5.42′ 1.67 L1 C C C CF₃ HH CF₃ H 359 5.78′ 2.01 L1 C C C H H F H H 241 5.09′ 2.02 L1 C C C Cl HCl H H 291/293 6.48′ 2.03 L1 C C C H NH₂ H CO₂Me H 2.96 3.51′ 3.01 L1 CC C H NH₂ Br H H 316/318 4.72′ 4.01 L1 C C C H CH₂NH— H H H 332 4.10′CH₂(2- furanyl) 4.04 L1 C C C OMe H H CH₂NHCH₂ H 362 4.24′ (2-furanyl)4.05 L1 C C C H CH₂NH— H H H 356 4.48′ (CH₂)₂Ph 4.07 L1 C C C OMe H HCH₂NH— H 386 4.70′ (CH₂)₂Ph 4.08 L1 C C C H CH₂NH— H H H 310 4.56′CH₂CH— (OH)CH₃ 4.09 L1 C C C OMe H H CH₂NHCH₂— H 340 3.86′ CH(OH)— CH₃4.12 L1 C C C H CH₂NH- H H H 324 3.72′ (n-Pr) 4.13 L1 C C C MeO H HCH₂NH- H 324 3.98′ (n-Pr) 4.14 L1 C C C MeO H H CH₂NH- H 322 3.92′cyclopropyl 4.15 L1 C C C H CH₂NH- H H H 292 3.67′ cyclo- propyl 4.18 L1C C C H CH₂NH— H H H 326 4.17′ CH₂CH— (OH)CH₂— OH 4.19 L1 C C C MeO H HCH₂NHCH₂ H 356 3.69′ —CH(OH)— CH₂OH 4.22 L1 C C C H CH₂NH— H H H 3424.40′ CH₂Ph 4.27 L1 C C C H CH₂NH— H H H 370 4.70′ (CH₂)₃Ph 4.28 L1 C CC MeO H H CH₂NH— H 400 4.90′ (CH₂)₃Ph 4.30 L1 C C C H CH₂NH- H H H 3364.69′ n-hexyl 4.32 L1 C C C H CH₂NH— H H H 384 4.95′ (CH₂)₄Ph 4.33 L1 CC C H CH₂NH— H H H 324 3.77′ (CH₂)₃OMe 4.36 L1 C C C H CH₂NH— H H H 3083.94′ isobutyl 4.37 L1 C C C OMe H H CH₂NH— H 338 4.20′ isobutyl 4.39 L1C C C H CH₂NH— H H H 324 3.72′ CH— (CH₂OH)Et 4.40 L1 C C C OMe H HCH₂NHCH— H 354 3.96′ (CH₂OH)Et 4.43 L1 C C C MeO H H CH₂NH— H 370 3.85′(CH₂)₂— O(CH₂)₂OH 4.46 L1 C C C MeO H H CH₂NHPh H 358 5.28′ 4.47 L1 C CC H H H CH₂NHPh H 328 6.10′ 4.48 L1 C C C MeO H H CH₂NH(4- H 374 5.58′hydroxy- phenyl) 4.49 L1 C C C MeO H H CH₂NH(4- H 373 4.16′ aminophenyl)4.50 L1 C C C MeO H H CH₂NH(4- H 415 4.28′ acetamido- phenyl) 4.51 L1 CC C MeO H H CH₂N(Ac)- H 415 4.29′ (4-amino- phenyl) 4.52 L1 C C C H H HCH₂NH— H 324 3.82′ (CH₂)₂—OEt 4.53 L1 C C C H H H CH₂NH- H 369 5.80(benzo- triazol-5-yl) 4.54 L1 C C C H H H H CH₂(3,4- 372 4.47′methylene- dioxyanil- ine-N-yl) 4.55 L1 C C C H H MeO H CH₂(3,4- 4025.44′ methylene- dioxyanil- ine-N-yl) 4.56 L1 C C C MeO H H CH₂NH- H 4484.90′ (3,4,5- trimethoxy- phenyl) 5.03 L1 C C C H C(O)NH- H H H 3865.52′ (2-(2- hydroxyethyl)- phenyl) 5.04 L1 C C N H C(O)NH- H null H 3877.00′ (2-(2- hydroxyethyl)- phenyl) 5.07 L1 C C C H H C(O)NH- H H 3726.66′ (3- (hydroxy- methyl)- phenyl) 5.10 L1 C C C C(O)NH- H H H H 3934.42′ (quin-olin-3- yl) 5.13 L1 C C C C(O)NH- H H H H 358 4.62′(4-hydroxy- phenyl) 5.14 L1 C C C C(O)(3,4- H H H H 386 5.50′ methylene-dioxy- anilinyl) 5.15 L1 C C C H H C(O)(3,4- H H 386 5.89′ methylene-dioxy- anilinyl) 5.16 L1 C C C C(O)NH- H H H H 385 4.34′ ((4-C(O)—NH₂)—C₆H₄) 5.19 L1 C C C C(O)NH— H H H H 350 6.04′ (CH₂)₂(tert- butyl)5.21 L1 C C C C(O)NH- H H H H 336 5.72′ n-pentyl 5.22 L1 C C C C(O)NH- HH H H 350 5.96′ n-hexyl 5.23 L1 C C C C(O)NH— H H H H 370 5.83′ (CH₂)₂Ph5.27 L1 C C C C(O)NH— H H H H 384 6.28′ (CH₂)₃Ph 5.29 L1 C C C C(O)NH— HH H H 398 6.70′ (CH₂)₄Ph 5.31 L1 C C C C(O)NH— H H H H 310 3.57′(CH₂)₂OH 5.33 L1 C C C C(O)NH— H H H H 354 3.84′ (CH₂)₂O— (CH₂)₂OH 5.35L1 C C C C(O)NH— H H H H 309 2.50′ (CH₂)₂NH₂ 5.36 L1 C C C H C(O)NH— H HH 309 3.45′ (CH₂)₂NH₂ 5.38 L1 C C C C(O)NH— H H H H 379 3.26′ (CH₂)₂-(morpholin- N-yl) 5.39 L1 C C C H C(O)NH— H H H 379 3.66′ (CH₂)₂-(morpholin- N-yl) 5.40 L1 C C C C(O)NH- H H H H 400 5.46′ piperonyl 5.41L1 C C C H C(O)NH- H H H 400 5.82′ piperonyl 5.43 L1 C C C C(O)NHCH₂- HH H H 350 5.97′ (tetrahydro- furan-2-yl) 5.44 L1 C C C H C(O)NH— H H H350 5.71′ CH₂- (tetrahydro furan-2-yl) 5.45 L1 C C C H H C(O)NH— H H 3504.58′ CH₂- (tetrahydro furan-2-yl) 5.48 L1 N C C H null H C(O)NH— H 3514.16′ CH₂- (tetrahydro- furan-2-yl) 5.49 L1 C C C H C(O)NH— H H H 3486.40′ (cyclo- hexyl) 5.51 L1 C C C C(O)NH— H H H H 323 3.43′ CH₂C(O)NH₂5.52 L1 C C C C(O)N(Me)— H H H H 385 4.14′ CH₂(6- methyl-2- pyridyl)5.53 L1 C C C C(O)(morpho- H H H H 336 4.49′ line amide) 6.01 L1 C C C HNHC(O)(3- H CO₂Et H 492/494 6.58′ Br-phenyl) 6.02 L1 C C C H NHC(O)(3- HCO₂-i-Pr H 506/508 6.63′ Br-phenyl) 6.03 L1 C C C H NHC(O)(3- H CO₂-n-BuH 520/522 6.93′ Br-phenyl) 6.04 L1 C C C H NHC(O)(3- H CO₂—(CH₂)₂— H522/524 6.58′ Br-phenyl) OMe 6.05 L1 C C C H NHC(O)(3- H CO₂—CH₂- H532/534 7.00′ Br-phenyl) cyclobutyl 8.02 L1 C C C H Br H H H 292/2944.58′ 8.03 L1 C C C H Br MeO H H 322/324 4.64′ 8.04 L1 C C C H Br H Br H370/372/ 5.33′ 374 8.05 L2 C C C Cl H H Br H 326/328 4.88′ 8.06 L2 C C COH Cl H Cl H 298/300 5.99′ 8.07 L2 C C C H H Br H H 292/294 4.88′ 8.08L2 C C C H H Me H H 228 4.36′ 8.09 L2 C C C Me H Br H H 306/308 4.97′8.10 L2 C C C H H I H H 340 5.07′ 8.13 L2 C C C H I H H H 340 5.04′ 8.14L2 C C C H NO₂ H NO₂ H 304 3.92′ 9.01 L2 C C C NH₂ Cl H H H 263 4.48′10.01 L3 C C C H H Br H H 292/294 4.91′ 10.02 L3 C C C OH H H NO₂ H 2754.54′ 10.03 L3 C C C OH H H H H 230 4.96′ 10.04 L3 C C C H Cl H Cl H 2835.70′ 10.05 L3 C C C H Me H Me H 242 5.13′ 10.06 L3 C C C H Cl Me H H262 5.30′ 10.07 L3 C C C H Cl H H H 248 4.82′ 10.08 L3 C C C H I H H H340 5.36′ 10.09 L3 C C C NH₂ H Cl Cl H 297/299 4.44′ 10.10 L3 C C C H HCl H H 248 4.90′ 10.11 L3 C C C H H F H H 232 4.30′ 10.12 L3 C C C H H IH H 340 5.44′ 11.01 L4 C C C MeO H Cl H H 279 5.21′ 11.03 L4 C C C H MeH H H 229 4.30′ 11.04 L4 C C C H H F H H 233 4.00′ 11.05 L4 C C C MeO HH Cl H 279 4.36′ 11.06 L4 C C C Ph H H H H 291 6.04′ 11.07 L4 N C C Hnull H Br H 294/296 4.33′ 11.08 L4 N C C Cl null CI H H 284/286 3.40′12.01 L4 C C C OMe Br H H H 323/325 4.93′ 13.01 L5 C C C H MeO Br H H309/311 5.24′ 13.02 L5 C C C H NO₂ H NO₂ H 291 4.34′ 15.01 L6 C C C NH₂H t-butyl H H 258 4.45′ 16.01 L7 C C C H H H H H 181 3.75′

TABLE 2

Table 2 cmpd M-1 no. L G² G³ G⁴ J² J³ J⁴ J⁵ found HPLC Rt 1.58 L1 C S CH null H CH₃ 243 5.38 4.02 L1 C S C CH₂NHCH₂ null H H 338 4.03′(2-furanyl) 4.03 L1 O C C null CH₂NHCH₂ H H 322 3.46′ (2-furanyl) 4.06L1 O C C null CH₂NH— H H 346 4.14′ (CH₂)₂Ph 4.10 L1 C S C CH₂NHCH₂— nullH H 316 3.52′ CH(OH)CH₃ 4.11 L1 O C C null CH₂NHCH₂— H H 300 4.04′CH(OH)CH₃ 4.16 L1 C S C CH₂NH- null H H 298 3.70′ cyclopropyl 4.17 L1 CS C CH₂NHCH₂CH— null H H 332 4.03′ (OH)CH₂OH 4.20 L1 O C C nullCH₂NHCH₂— H H 316 3.58′ CH(OH)— CH₂OH 4.21 L1 O C C null CH₂NHCH₂Ph H H332 3.91′ 4.23 L1 O C C null CH₂NH— H H 300 3.99′ (CH₂)₃OH 4.24 L1 C S CCH₂NH— null H H 316 3.42′ (CH₂)₃OH 4.25 L1 O C C null CH₂NH- H H 3124.12′ (n-pentyl) 4.26 L1 O C C null CH₂NH— H H 360 4.49′ (CH₂)₃Ph 4.29L1 O C C null CH₂NH-n-hexyl H H 326 4.48′ 4.31 L1 O C C null CH₂NH— H H374 4.73′ (CH₂)₄Ph 4.34 L1 C S C CH₂NH— null H H 330 3.89′ (CH₂)₃OMe4.35 L1 O C C null CH₂NH— H H 314 4.04′ (CH₂)₃OMe 4.38 L1 O C C nullCH₂NH-isobutyl H H 298 4.26′ 4.41 L1 O C C null CH₂NHCH— H H 314 4.46′(CH₂OH)Et 4.42 L1 O C C null CH₂NH(CH₂)₂— H H 341 3.61′ N(Et)₂ 4.44 L1 OC C null CH₂NH(CH₂)₂— H H 330 3.46′ O(CH₂)₂OH 4.45 L1 O C C nullCH₂NH(CH₂)₂— H H 326 4.26′ tert-butyl 5.01 L1 C S C C(O)NH(2-(2- null HH 392 5.17′ hydroxyethyl)- phenyl) 5.02 L1 C S C C(O)N(Me)- null H H 3665.28′ CH₂(2-furyl) 5.05 L1 O C C null C(O)NH(2-(2- H H 376 5.17′hydroxyethyl)- phenyl) 5.06 L1 C S C C(O)NH- null H H 378 6.36′(3-(hydroxy- methyl)phenyl) 5.08 L1 C S C C(O)NH- null H H 399 4.38′(quinolin-8-yl) 5.09 L1 C S C C(O)NH- null H H 399 5.49′ (quinolin-3-yl)5.11 L1 C S C C(O)NH- null H H 391 4.79′ (3-carbamoyl- phenyl) 5.12 L1 CS C C(O)NH(4- null H H 364 4.70′ hydroxyphenyl) 5.17 L1 C S C C(O)NH-null H H 312 4.14′ cyclopropyl 5.18 L1 C S C C(O)NH-tert- null H H3285.12′ butyl 5.20 L1 C S C C(O)NH- null H H 356 6.06′ (CH₂)₂(tert-butyl)5.23 L1 C S C C(O)NH-n-hexyl null H H 356 6.42′ 5.24 L1 C S C C(O)NHBnnull H H 362 5.57′ 5.26 L1 C S C C(O)NH— null H H 376 5.88′ (CH₂)₂Ph5.28 L1 C S C C(O)NH— null H H 390 6.26′ (CH₂)₃Ph 5.30 L1 C S C C(O)NH—null H H 404 6.36′ (CH₂)₄Ph 5.32 L1 C S C C(O)NH— null H H 316 3.57′(CH₂)₂OH 5.34 L1 C S C C(O)NH— null H H 358 4.88′ (CH₂)₃OEt 5.37 L1 C SC C(O)NH— null H H 315 3.22′ (CH₂)₂NH₂ 5.42 L1 C S C null C(O)NH- H H406 5.86′ piperonyl 5.46 L1 C S C C(O)NHCH₂- null H H 356 4.54′(tetrahydrofuran- 2-yl) 5.47 L1 C S C null C(O)NHCH₂- H H 356 4.58′(tetrahydrofuran- 2-yl) 5.5 L1 C S C C(O)NH- H H H 354 5.86′(cyclohexyl) 7.01 L1 O C N null Me null isobutyl 284 5.04′ 8.01 L2 O C Cnull Br H H 282/284 3.72′ 8.11 L2 C O C H null H H 204 4.13′ 8.12 L2 S CC null Br H H 298/300 4.62′ 11.02 L4 O C C null Br H H 283/285 2.39′14.01 L5 S C N null Cl null Cl 276/278 4.36′Synthesis of Compounds of Formula I

Synthesis of compounds encompassed by the present invention typicallyincludes some or all of the following general steps as represented inthe scheme below: (a) coupling of a phosphonate fragment (1a or 1b) withan aryl or heteroaryl ring fragment (2a or 2b, respectively); (b)modification of the coupled molecule if necessary; (c) deprotection of aphosphonate diester (3) to give a phosphonic acid (4) and (d)preparation of a phosphonate prodrug.

(a) Coupling of a phosphonate fragment (1) with an aryl moiety (2).

When feasible, compounds disclosed in the present invention areadvantageously prepared via a convergent synthetic route entailing thecoupling of a phosphonate component with an aryl or heteroaryl ringfragment.

Transition metal-catalyzed coupling reactions such as Stille and Suzukireactions are particularly suited for the synthesis of compounds offormula I (Farina et al, Organic Reactions, Vol. 50; Wiley, New York,1997; Suzuki in Metal Catalyzed Cross-Coupling Reactions; Wiley VCH,1998, pp 49-97). Coupling reactions between a compound 1 (wherein B ispreferably a Bu₃Sn) and a compound 2 (wherein A is e.g. an iodo, bromoor trifluoromethylsulfonate) under palladium-catalyzed reactionconditions to yield compounds of formula 3 wherein L is e.g. a2,5-furanyl. The same type of coupling between a compound 1 (wherein Bis preferably an iodo group) and a compound 2 (wherein A=B(OH)₂ or aBu₃Sn) can also be used to yield compounds of formula 3 wherein L ise.g. a 2,5-furanyl.

The reactants 2 that are substituted aryl and heteroaryl compounds areeither commercially available or readily synthesized using knownmethodology. The coupling agents 1 are also prepared using well-knownchemistry. For example when L is a 2,5-furanyl, the coupling agent 1 isprepared starting from furan using organolithium techniques. Lithiationof furan using known methods (e.g. n-BuLi/TMEDA, Gschwend Org. React.1979, 26: 1) followed by addition of phosphorylating agents (e.g.ClPO₃R₂) give 2-dialkylphosphono-furans (e.g. 2-diethylphosphonofuran).Synthesis of 2,5-disubstituted furan building blocks can be completed bylithiation of a 2-dialkylphosphonofuran (eg. 2-diethylphosphonofuran)with a suitable base (e.g. LDA) followed by trapping of the generatedanion with an electrophile (e.g. with tributyltinchloride, triisopropylborate or iodine) to produce a 5-functionalized-2-dialkylphosphonofuran(e.g. 5-tributylstannyl-2-diethylphosphonofuran,2-diethylphosphonofuran-5-boronic acid or5-iodo-2-diethylphosphonofuran, respectively).

It is envisioned that the above described methods for the synthesis offuran derivatives can be either directly or with some modificationsapplied to syntheses of various other useful intermediates such as arylphosphonate esters (e.g. thienyl phosphonate esters, phenyl phosphonateesters or pyridyl phosphonate esters).

Known amide bond formation reactions can be used to couple a phosphonatediester building block 1 with an aryl or heteroaryl ring intermediate 2leading to compounds of formula I wherein L is a alkylaminocarbonyl oran alkylcarbonylamino group. For example, coupling of an aryl carboxylicacid preferably with diethyl aminomethylphosphonate can result in acompound of formula I wherein the ring fragment incorporated fromintermediate 2 is an aryl and the L fragment is —CH₂NHC(O)—. Similarly,substitution of diethyl alkylaminoalkylphosphonates in this method mayproduce compounds with an L fragment represented by —R′C(R″)N(R)C(O)—.Alternatively, for example, coupling of an aryl amine preferably withdiethylphosphonoacetic acid can result in a compound of formula Iwherein the ring fragment incorporated from intermediate 2 is an aryland the L fragment is —CH₂C(O)NH—. Compounds with an L fragment of—R′C(R″)C(O)NR— may be prepared by extension of this method.

Known ester bond formation reactions can be used to produce compounds offormula I wherein L is alkylcarboxy or alkoxycarbonyl (e.g. —CH₂C(O)O—or —CH₂OC(O)—). For example, when compound 2 fragment is a hydroxysubstituted aryl (e.g. a phenol derivative) it can be acylated withdiethylphosphonoacetyl chloride in the presence of a hindered amine suchas triethylamine to produce compounds wherein L is —CH₂C(O)O—.Additionally, aryl-acyl halides (e.g. aryl-acyl chlorides) can becoupled to dialkyl (hydroxyalkyl)phosphonates (e.g. diethyl(hydroxy)methylphosphonate) to produce compounds wherein L is-alkoxycarbonyl- (e.g. —CH₂OC(O)—).

Known ether bond formation reactions can be used to produce compounds offormula I where L is an alkylene-O or an alkylene-O-alkylene group. Forexample, the sodium salt of a phenol may be alkylated withdiethyl(iodomethyl)phosphonate or preferably diethylphosphonomethyltriflate to produce compounds of formula I where L is -alkylene-O.Likewise, alkylation of the sodium salt of a arylmethyl alcohol withdiethyl (iodomethyl)phosphonate or preferably diethylphosphonomethyltriflate may produce compounds of formula I where L is-alkylene-O-alkylene-. Alternatively, treatment of diethylhydroxymethylphosphonate with sodium hydride and reaction of thisgenerated sodium salt with a haloalkylaryl compound can producecompounds of formula I where L is -alkylene-O-alkylene-.

For compounds of formula I wherein L is an alkyl group, the phosphonategroup can be introduced using other common phosphonate formation methodssuch as Michaelis-Arbuzov reaction (Bhattacharya et al., Chem. Rev.,1981, 81: 415), Michaelis-Becker reaction (Blackburn et al., J.Organomet. Chem., 1988, 348: 55), and addition reactions of phosphorusto electrephiles (such as aldehydes, ketones, acyl halides, imines andother carbonyl derivatives).

When feasible and sometimes advantageous, compounds of formula 3 canalso be prepared from an aryl compound (2b) via the introduction of aphosphonate moiety such as a dialkylphosphono group (e.g. adiethylphosphono group). For example, compounds of formula I wherein Lis a 1,2-ethynyl can be prepared via the lithiation of a terminalarylalkyne followed by reacting the anion with a phosphorylating agent(e.g. CtPO₃R₂) to give an arylalkynylphosphonate. The requiredarylalkynes are readily made using conventional chemistry. For example,arylalkynes can be derived from reactions of aryl halides (e.g. iodides,bromides) or triflates and trimethylsilylacetylene using Sonogashirareactions (Sonogashira in Comprehensive Organic Synthesis, PergamonPress: New York, 1991, vol. 3, pp 521-549) followed by deprotection ofthe trimethylsilyl group to give terminal arylalkynes.

(b) Modification of the Coupled Molecule.

The coupled, molecule 3 can be modified in a variety of ways. Arylhalides (J²-J⁶ each optionally e.g. Br, I or O-triflate) are usefulintermediates and are often readily converted to other substituents suchas aryls, olefins, alkyls, alkynyls, arylamrines and aryloxy groups viatransition metal assisted coupling reactions such as Stille, Suzuki,Heck, Sonogashira and other reactions (Farina et al, Organic Reactions,Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzukiin Metal Catalyzed Cross-Coupling Reactions; Wiley VCH, 1998, pp 49-97;Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego,1985; Sonogashira in Comprehensive Organic Synthesis, Pergamon Press:New York, 1991, vol. 3, pp 521-549, Buchwald J. Am. Chem. Soc. 1999,121, 4369-4378; Hartwig, J. Am. Chem. Soc. 1999, 121, 3224-3225;Buchwald Acc. Chem. Res. 1998, 31, 805).

Compounds of formula I wherein J²-J⁶ are each optionally is acarboxamido group can be made from their corresponding alkyl carboxylateesters via aminolysis using various amines, or by reaction of carboxylicacids with amines under standard amide bond formation reactionconditions (e.g.: DIC/HOBt mediated amide bond formation).

Compounds of formula I wherein J²-J⁶ are each optionally a carboxylateester group can be made from the corresponding carboxylic acids bystandard esterification reactions (e.g. DIEA/DMF/alkyl iodide or EDCI,DMAP and an alcohol), or from the corresponding aryl halides/triflatesvia transition metal-catalyzed carbonylation reactions.

Compounds of formula I wherein J²-J⁶ are each optionally is analkylaminoalkyl or arylaminoalkyl group can be prepared from theircorresponding aldehydes by standard reductive amination reactions (e.g.aryl or alkyl amine, TMOF, AcOH, DMSO, NaBH₄).

(c) Deprotection of a Phosphonate or Phosphoramidate Ester

Compounds of formula 4 may be prepared from phosphonate esters usingknown phosphate and phosphonate ester cleavage conditions. Silyl halidesare generally used to cleave various phosphonate esters. When required,acid scavengers (e.g. 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidineetc.) can be used for the synthesis of acid labile compounds. Such silylhalides include preferably bromotrimethylsilane (McKenna, et al,Tetrahedron Lett., 1977, 155), chlorotrimethylsilane (Rabinowitz, J.Org. Chem., 1963, 28: 2975) and iodotrimethylsilane (Blackburn, et al, JChem. Soc., Chem. Commun., 1978, 870). Alternately, phosphonate esterscan be cleaved under strong acidic conditions (e.g. HBr, HCl: Moffatt,et al, U.S. Pat. No. 3,524,846, 1970). Aryl and benzyl phosphonateesters can be cleaved under hydrogenolysis conditions (Lejczak, et al,Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985, 28: 1208;Baddiley, et al, Nature, 1953, 171, 76).

(d) Preparation of a Phosphonate or Phosphoramidate Prodrug

The prodrug substitution can be introduced at different stages of thesynthesis. Most often the prodrug is made from the phosphonic acid offormula 4 because of the instability of some of the prodrugs.Advantageously, the prodrug can be introduced at an earlier stage,provided that it can withstand the reaction conditions of the subsequentsteps.

Bis-phosphoramidates, compounds of formula I wherein both Y's arenitrogen and R¹′s are identical groups derived from amino acids, can beprepared from compounds of formula 4 via the coupling of a suitablyactivated phosphonate (e.g. dichlorophosphonate) with an amino acidester (e.g. alanine ethyl ester) with or without the presence of a base(e.g. N-methylimidazole, 4-N,N-dimethylaminopyridine). Alternatively,bis-phosphoramidates can be prepared through reactions between compoundsof formula 4 with an amino acid ester (e.g. glycine ethyl ester) in thepresence of triphenylphosphine and 2,2′-dipyridyl disulfide in pyridineas described in WO 95/07920 or Mukajyama, T. et al, J Am. Chem. Soc.,1972, 94, 8528.

Mixed bis-phosphoramidates, compounds of formula I wherein both Y's arenitrogen and R¹′s are different groups with one R¹ being derived fromamino acids and the other R¹ being either derived from amino acids orother groups (e.g. alkyl, aryl, arylalkyl amines), can be prepared bythe methods described above but with sequential addition of thedifferent amines (e.g. a glycine ethyl ester and an alanine ethyl ester)to a suitably activated phosphonates (e.g. dichlorophosphonate). It isanticipated that the mixed bis-phosphoramidates may have to be separatedfrom other products (e.g. compounds of formula I wherein both Y's arenitrogen and R¹′s are identical-groups) using suitable purificationtechniques such as column chromatography, MPLC or crystallizationmethods. Alternatively, mixed bis-phosphoramidates can be prepared inthe following manner: coupling of an appropriate phosphonate monoester(e.g. phenyl esters or benzyl esters) with an amine (e.g. alanine ethylester or morpholine) via the chloridate method described above, followedby removal of the phosphonate ester (e.g. phenyl esters or benzylesters) under conditions that the phosphoramidate bond is stable (e.g.suitable hydrogenation conditions), and the resultingmono-phosphoramidate can be coupled with a second amine (e.g. glycineethyl ester) to give a mixed bis-phosphoramidate via the chloridatemethod described above. Mono esters of a phosphonic acid can be preparedusing conventional methods (e.g. hydrolysis of phosphonate diesters orprocedures described in EP 481 214).

Mono phosphoramidate mono esters, compounds of formula I wherein one Yis O and the other Y is N, can also be prepared using the sequentialaddition methods described above. For example, a dichloridate generatedfrom compounds of formula 4 can be treated with 0.7 to 1 equivalent ofan alcohol (e.g. phenol, benzyl alcohol, 2,2,2-trifluoroethanol)preferably in the presence of a suitable base (e.g. Hunig's base,triethylamine). After the above reaction is completed, 2 to 10equivalents of an amine (e.g. alanine ethyl ester) is added to thereaction to give compounds of formula I wherein one Y is O and the otherY is N. Alternatively,.selective hydrolysis (e.g. using lithiumhydroxide) of a phosphonate diester (e.g. a diphenyl phosphonate) canalso lead to a phosphonate mono ester (e.g. a phosphonate mono phenylester), and the phosphonate mono ester can be coupled with an amine(e.g. alanine ethyl ester) via the chloridate method described above forthe preparation of mixed bis-phosphoramidates.

Compounds of formula 4, can be alkylated with electrophiles (such asalkyl halides, alkyl sulfonates, etc.) under nucleophilic substitutionreaction conditions to give phosphonate esters. For example compounds offormula I, wherein R¹ are acyloxyalkyl groups can be synthesized throughdirect alkylation of compounds of formula 4 with an appropriateacyloxyalkyl halide (e.g. Cl, Br, I; Elhaddadi, et al Phosphorus Sulfur,1990, 54(1-4): 143; Hoffmann, Synthesis, 1988, 62) in presence of asuitable base (e.g. N,N′-dicyclohexyl-4-morpholinecarboxamidine, Hunig'sbase etc.) (Starrett, et al, J. Med. Chem., 1994, 1857). The carboxylatecomponent of these acyloxyalkyl halides can be, but is not limited to,acetate, propionate, 2-methylpropionate, pivalate, benzoate, and othercarboxylates. When appropriate, further modifications are envisionedafter the formation of acyloxyalkyl phosphonate esters such as reductionof a nitro group. For example, compounds of formula 5 wherein J² to J⁶are each optionally a nitro group can be converted to compounds offormula 5 wherein J²to J⁶ are each optionally an amino group undersuitable reduction conditions (Dickson, et al, J. Med. Chem., 1996, 39:661; Iyer, et al, Tetrahedron Lett., 1989, 30: 7141; Srivastva, et al,Bioorg Chem., 1984, 12: 118). Compounds of formula I wherein R¹ is acyclic carbonate, a lactone or a phthalidyl group can also besynthesized via direct alkylation of compounds of formula 4 withappropriate electrophiles (e.g. halides) in the presence of a suitablebase (e.g. NaH or diisopropylethylamine, Biller et al., U.S. Pat. No.5,157,027; Serafinowska et al., J. Med. Chem. 1995, 38: 1372; Starrettet al., J. Med. Chem. 1994, 37: 1857; Martin et al., J. Pharm. Sci.1987, 76: 180; Alexander et al., Collect. Czech. Chem. Commun, 1994, 59:1853; EPO 0632048A1). Other methods can also be used to alkylatecompounds of formula 4 (e.g. using N,N-Dimethylformamide dialkyl acetalsas alkylating reagents: Alexander, P., et al Collect. Czech. Chem.Commun., 1994, 59, 1853).

Alternatively, these phosphonate prodrugs can -also be synthesized byreactions of the corresponding dichlorophosphonates with an alcohol(Alexander et al, Collect. Czech. Chem. Commun., 1994, 59: 1853). Forexample, reactions of a dichlorophosphonate with substituted phenols,arylalkyl alcohols in the presence of a suitable base (e.g. pyridine,triethylamine, etc) yield compounds of formula I where R¹ is an arylgroup (Khamnei et al., J. Med. Chem., 1996, 39: 4109; Serafinowska etal., J. Med. Chem., 1995, 38: 1372; De Lombaert et al., J. Med. Chem.,1994, 37: 498) or an arylalkyl group (Mitchell et al., J. Chem. Soc.Perkin Trans. 1, 1992, 38: 2345) and Y is oxygen. Thedisulfide-containing prodrugs (Puech et al., Antiviral Res., 1993, 22:155) can also be prepared from a dichlorophosphonate and 2-hydroxyethyldisulfide under standard conditions. When applicable, these methods canbe extended to the synthesis of other types of prodrugs, such ascompounds of formula I wherein R¹ is a 3-phthalidyl, a2-oxo-4,5-didehydro-1,3-dioxolanemethyl, or a 2-oxotetrahydrofuran-5-ylgroup.

A dichlorophosphonate or a monochlorophosphonate derivative of compoundsof formula 4 can be generated from the corresponding phosphonic acidsusing a chlorinating agent (e.g. thionyl chloride: Starrett et al., J.Med. Chem., 1994, 1857, oxalyl chloride: Stowell et al., TetrahedronLett., 1990, 31: 3261, and phosphorus pentachloride: Quast et al.,Synthesis, 1974, 490). Alternatively, a dichlorophosphonate can also begenerated from its corresponding disilyl phosphonate esters (Bhongle etal., Synth. Commun., 1987, 17: 1071) or dialkyl phosphonate esters(Still et al., Tetrahedron Lett., 1983, 24: 4405; Patois et al., Bull.Soc. Chim. Fr., 1993, 130: 485).

Furthermore, when feasible some of these prodrugs can be prepared usingMitsunobu reactions (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org.Chem., 1992, 52: 6331), and other coupling reactions (e.g. usingcarboduimides: Alexander et al., Collect. Czech. Chem. Common., 1994,59: 1853; Casara et al., Bioorg. Med. Chem. Lett., 1992, 2: 145; Ohashiet al., Tetrahedron Lett., 1988, 29: 1189, andbenzotriazolyloxytris-(dimethylamino)phosphonium salts: Campagne et al.,Tetrahedron Lett., 1993, 34: 6743). In some cases R¹ can also beintroduced advantageously at an early stage of the synthesis providedthat it is compatible with the subsequent reaction steps. For example,compounds of formula I where R¹ is an aryl group can be prepared bymetalation of a 2-furanyl substituted heterocycle (e.g. using LDA)followed by trapping the anion with a diaryl chlorophosphate.

It is envisioned that compounds of formula I can be mixed phosphonateesters (e.g. phenyl and benzyl esters, or phenyl and acyloxyalkylesters) including the chemically combined mixed esters such as thephenyl and benzyl combined prodrugs reported by Meier, et al. Bioorg.Med. Chem. Lett., 1997, 7: 99.

The substituted cyclic propyl phosphonate or phosphoramidate esters canbe synthesized by reactions of the corresponding dichlorophosphonatewith a substituted 1,3-propanediol, 1,3-hydroxypropylamine,.or1,3-propanediamine. Some of the methods useful for preparations of asubstituted 1,3-propanediol, for example, are discussed below.

Synthesis of a 1,3-propanediol, 1,3-hydroxypropylamine and1,3-propanediamine

Various synthetic methods can be used to prepare numerous types of1,3-propanediols: (i) 1-substituted, (ii) 2-substituted, (iii) 1,2- or1,3-annulated 1,3-propanediols, (iv) 1,3-hydroxypropylamine and1,3-propanediamine. Substituents on the prodrug moiety of compounds offormula I (e.g. substituents on the 1,3-propanediol moiety) can beintroduced or modified either during the synthesis of thesediols,hydroxyamines, and diamines, or after the coupling of thesecompounds to the compounds of formula 4.

(i) 1-Substituted 1,3-propanediols.

1,3-Propanediols useful for the synthesis of compounds in the presentinvention can be prepared using various synthetic methods. For example,additions of an aryl Grignard to a 1-hydroxy-propan-3-al give 1-arylsubstituted 1,3-propanediols (path a). This method is suitable for theconversion of various aryl halides to 1-arylsubstituted-1,3-propanediols (Coppi et. al., J. Org. Chem., 1988, 53,911). Conversions-of aryl halides to 1-substituted 1,3-propanediols canalso be achieved using Heck reactions (e.g. couplings with a1,3-diox-4-ene) followed by reductions and subsequent hydrolysisreactions (Sakamoto et. al., Tetrahedron Lett., 1992, 33, 6845). Variousaromatic aldehydes can also be converted to1-substituted-1,3-propanediols using alkenyl Grignard addition reactionsfollowed by hydroboration reactions (path b). Additions of a t-butylacetate metal enolate to aromatic aldehydes followed by reduction of theester (path e) are also useful for the synthesis of 1,3-propanediols(Tumer., J. Org. Chem., 1990, 55 4744). In another method, epoxidationsof cinnamyl alcohol derivatives using known methods (e.g. Sharplessepoxidations and other asymmetric epoxidation reactions) followed by areduction reaction (e.g. using Red-Al) give various 1,3-propanediols(path c). Alternatively, enantiomerically pure 1,3-propanediols can beobtained using chiral borane reduction reactions of hydroxyethyl arylketone derivatives (Ramachandran et. al., Tetrahedron Lett., 1997, 38761). Propan-3-ols with a 1-heteroaryl substituent (e;g. a pyridyl, aquinolinyl or an 10 isoquinolinyl) can be oxygenated to give1-substituted 1,3-propanediols using N-oxide formation reactionsfollowed by a rearrangement reaction in acetic anhydride conditions(path d) (Yamamoto et. al., Tetrahedron ,1981, 37, 1871).

(ii) 2-Substituted 1,3-propanediols:

A variety of 2-substituted 1,3-propanediols useful for the synthesis ofcompounds of formula I can be prepared from2-(hydroxymethyl)-1,3-propanediols using known chemistry (Larock,Comprehensive Organic Transformations, VCH, New York, 1989). Forexample, reductions of a trialkoxycarbonylmethane under known conditionsgive a triol via complete reduction (path a) or abis(hydroxymethyl)acetic acid via selective hydrolysis of one of theester group followed by reduction of the remaining two other estergroups. Nitrotriols are also known to give triols via reductiveelimination (path b) (Latour et. al., Synthesis, 1987, 8, 742).Furthermore, a 2-(hydroxymethyl)-1,3-propanediol can be converted to amono acylated derivative (e.g. acetyl, methoxycarbonyl) using an acylchloride or an alkyl chloroformate (e.g. acetyl chloride or methylchloroformate) (path d) using known chemistry (Greene et al., Protectivegroups in organic synthesis; Wiley, New York, 1990). Other functionalgroup manipulations can also be used to prepare 1,3-propanediols such asoxidation of one the hydroxylmethyl group in a2-(hydroxymethyl)-1,3-propanediol to an aldehyde followed by additionreactions with an aryl Grignard (path c). The intermediate aldehydes canalso be converted to alkyl amines via reductive amination reactions(path e).

(iii) Annulated 1,3-Propane Diols:

Compounds of formula I wherein V and Z or V and W are connected by fourcarbons to form a ring can be prepared from a 1,3-cyclohexanediol. Forexample, cis, cis-1,3,5-cyclohexanetriol can be modified as describedfor 2-substituted 1,3-propanediols. It is envisioned that thesemodifications can be performed either before or after formation of acyclic phosphonate 1,3-propanediol ester. Various 1,3-cyclohexanediolscan also be prepared using Diels-Alder reactions (e.g. using a pyrone asthe diene: Posner et. al., Tetrahedron Lett., 1991, 32, 5295).1,3-Cyclohexanediol derivatives are also prepared via othercycloaddition reaction methodologies. For example, cycloadditon of anitrile oxide to an olefin followed by conversion of the resultingcycloadduct to a 2-ketoethanol derivative which can be converted to a1,3-cylohexanediol using know chemistry (Curran, et. al., J. Am. Chem.Soc., 1985, 107, 6023). Alternatively, precursors to 1,3-cyclohexanediolcan be made from quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32,547.)

(vi) Synthesis of Chiral Substituted 1,3-Hydroxyamines and 1,3-Diamines:

Enantiomerically pure 3-aryl-3-hydroxypropan-1-amines are synthesized byCBS enantioselective catalytic reaction of 3-chloropropiophenonefollowed by displacement: of halo group to make secondary or primaryamines as required (Corey, et al., Tetrahedron Lett., 1989, 30, 5207).Chiral 3-aryl-3-amino propan-1-ol type of prodrug moiety may be obtainedby 1,3-dipolar addition of chirally pure olefin and substituted nitroneof arylaldehyde followed by reduction of resulting isoxazolidine(Koizumi, et al., J. Org. Chem., 1982, 47, 4005). Chiral induction in1,3-polar additions to form substituted isoxazolidines is also attainedby chiral phosphine palladium complexes resulting in enantioselectiveformation of δ-amino alcohol (Hori, et al., J. Org. Chem., 1999, 64,5017). Alternatively, optically pure 1-aryl substituted amino alcoholsare obtained by selective ring opening of corresponding chiral epoxyalcohols with desired amines (Canas et al., Tetrahedron Lett., 1991, 32,6931).

Several methods are known for diastereoselective synthesis of1,3-disubstituted aminoalcohols. For example, treatment of(E)-N-cinnamyltrichloroacetamide with hypochlorus acid results intrans-dihydrooxazine which is readily hydrolysed toerythro-β-chloro-α-hydroxy-δ-phenylpropanamine in highdiastereoselectivity (Commercon et al., Tetrahedron Lett., 1990, 31,3871). Diastereoselective formation of 1,3-aminoalcohols is alsoachieved by reductive amination of optically pure 3-hydroxy ketones(Haddad et al., Tetrahedron Lett., 1997, 38, 5981). In an alternateapproach, 3-aminoketones are transformed to 1,3-disubstitutedaminoalcohols in high stereoselectivity by a selective hydride reduction(Barluenga et al., J. Org. Chem., 1992, 57, 1219).

All the above mentioned methods can also be applied to preparecorresponding V-Z, V-W, or V²-Z² annulated chiral aminoalcohols.Furthermore, such optically pure amino alcohols are also a source toobtain optically pure diamines by the procedures described earlier inthe section.

Formulations

Compounds of the invention are administered orally in a total daily doseof about 0.01 mg/kg/dose to about 100 mg/kg/dose, preferably from about0.1 mg/kg/dose to about 1 0 0 mg/kg/dose. The use of time-releasepreparations to control the rate of release of the active ingredient maybe preferred. The dose may be administered in as many divided doses asis convenient. When other methods are used (e.g. intravenousadministration), compounds are administered to the affected tissue at arate from 0.05 to 10 mg/kg/hour, preferably from 0.1 to 1 mg/kg/hour.Such rates are easily maintained when these compounds are intravenouslyadministered as discussed below.

For the purposes of this invention, the compounds may be administered bya variety of means including orally, parenterally, by inhalation spray,topically, or rectally in formulations containing pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedhere includes subcutaneous, intravenous, intramuscular, andintraarterial injections with a variety of infusion techniques.Intraarterial and intravenous injection as used herein includesadministration through catheters. Oral administration is generallypreferred.

Pharmaceutical compositions containing the active ingredient may be inany form suitable for the intended method of administration. When usedfor oral use for example, tablets, troches, lozenges, aqueous or oilsuspensions, dispersible powders or granules, emulsions, hard or softcapsules, syrups or elixirs may be prepared. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as calcium or sodium carbonate,lactose, calcium or sodium phosphate; granulating and disintegratingagents, such as maize starch, or alginic acid; binding agents, such asstarch, gelatin or acacia; and lubricating agents, such as magnesiumstearate, stearic acid or talc. Tablets may be uncoated or may be coatedby known techniques including microencapsulation to delay disintegrationand adsorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate alone orwith a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a-fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g. polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more-coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring, agents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable; preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions. The pharmaceuticalcomposition can be prepared to provide easily measurable amounts foradministration. For example, an aqueous solution intended forintravenous infusion should contain from about 3 to 330 μg of the activeingredient per milliliter of solution-in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

As noted above, formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion ora water-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with abinder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose) surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropyl methylcellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach. This is particularly advantageous with thecompounds of formula I when such compounds are susceptible to acidhydrolysis.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerin, or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containantioxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Suitable unit dosage formulations are those containing a daily dose orunit, daily sub-dose, or an appropriate fraction thereof, of afructose-1,6-bisphosphatase inhibitor compound.

It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed; the age, body weight,general health, sex and diet of the individual being treated; the timeand route of administration; the rate of excretion; other drugs whichhave previously been administered; and the severity of the particulardisease undergoing therapy, as is well understood by those skilled inthe art.

Utility

FBPase inhibitors may be used to treat diabetes mellitus, lower bloodglucose levels, and inhibit gluconeogenesis.

FBPase inhibitors may also be used to treat excess glycogen storagediseases. Excessive hepatic glycogen stores are found in patients withsome glycogen storage diseases. Since the indirect pathway contributessignificantly to glycogen synthesis (Shulman, G. I. Phys. Rev.72:1019-1035 (1992)), inhibition of the indirect pathway(gluconeogenesis flux) decreases glycogen overproduction.

FBPase inhibitors may also be used to treat or prevent diseasesassociated with increased insulin levels. Increased insulin levels areassociated with an increased risk of cardiovascular complications andatherosclerosis (Folsom, et al., Stroke, 25:66-73 (1994); Howard, G. etal., Circulation 93:1809-1817 (1996)). FBPase inhibitors are expected todecrease postprandial glucose levels by enhancing hepatic glucoseuptake. This effect is postulated to occur in individuals that arenon-diabetic (or pre-diabetic, i.e. without elevated hepatic glucoseoutput “hereinafter HGO” or fasting blood glucose levels). Increasedhepatic glucose uptake will decrease insulin secretion and therebydecrease the risk of diseases or complications that arise from elevatedinsulin levels.

One aspect of the invention is directed to the use of prodrugs of thenovel aryl phosphonates or phosphoramidates which results in efficientconversion of the cyclic phosphonate or phosphoramidate. The cyclic1,3-propanyl ester containing compounds are oxidized by p450 enzymesfound in large amounts in the liver and other tissues containing thesespecific enzymes.

In another aspect of the invention, these prodrugs can also be used toprolong the pharmacodynamic half-life because the cyclic phosphonates orphosphoramidatess of the invention can prevent the action of enzymeswhich degrade the parent drug.

In another aspect of the invention, these prodrugs can be used toachieve sustained delivery of the parent drug because various novelprodrugs are slowly oxidized in the liver at different rates.

The novel cyclic 1,3-propanyl esters of the present invention may alsobe used to increase the distribution of a particular drug to the liverwhich contains abundant amounts of the p450 isozymes responsible foroxidizing the cyclic 1,3-propanyl ester of the present invention so thatthe free phosphonate or phosphoramidate is produced.

In another aspect of the invention, the cyclic phosphonate orphosphoramidate prodrugs can increase the oral bioavailability of thedrugs.

Theses aspects are described in greater detail below.

Evidence of the liver specificity can also be shown in vivo after bothoral and I.V. administration of the prodrugs as described in Examples Gand H.

Prodrug Cleavage Mechanism of Cyclic 1,3-Propanyl Esters

The cyclic 1,3-propanyl ester prodrugs are rapidly cleaved in thepresence of liver microsomes from rates and humans, by freshly isolatedrat hepatocyles, and by cytochrome P450 inhibitors. It is believed thatthe isoenzyme cytochrome CYP3A4 is responsible for the oxidation basedon ketoconozole inhibition of drug formation. Inhibitors of cytochromeP450 family 1 and/or family 2 do not appear to inhibit prodrug cleavage.Furthermore, although these specific prodrugs appear to be cleaved byCYP3A4, other prodrugs in the class may be substrates for other P450s.

Although the cyclic 1,3-propanyl esters in the invention are not limitedby the above mechanisms, in general, each ester contains a group or atomsusceptible:.to microsomal oxidation (e.g. alcohol, benzylic methineproton), which in turn generates an intermediate that breaks down to theparent compound in aqueous solution via β-elimination of the phosphonateor phosphoramidate diacid.

Class (1) prodrugs readily undergo P450 oxidation because they have aZ′=hydroxyl or hydroxyl equivalent with an adjacent (geminal) acidicproton. D′ is hydrogen to allow the ultimate elimination to produce aphenol.

Class (2) generally has V is selected from group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and1-alkynyl. This class of prodrugs readily undergoes P450 oxidation atthe benzylic methine proton (the proton on the carbon to which V isattached). The allylic proton In the-case of 1-alkenyl and 1-alkynylbehaves similarly. There must be a hydrogen geminal to V to undergo thisoxidation mechanism. Because Z, W, and W′ are not at the oxidation sitein this class of prodrugs, a broad range of substituents are possible.In one aspect, Z can be an electron donating group which may reduce themutagenicity or toxicity of the arylvinyl ketone that is the by-productof the oxidation of this class of prodrugs. Thus, in this aspect Z is—OR², —SR², or 2NR² ₂.

In this class of prodrug, V and W may be cis to one another or trans toone another. The class (2) mechanism generally describes the oxidationmechanism for cyclic 1,3-propanyl esters wherein together V and Z areconnected via an additional 3-5 atoms to form a cyclic group, optionallycontaining 1 heteroatom, said cyclic group is fused to an aryl group atthe beta and gamma position to the Y adjacent to V.

Class (3) includes compounds wherein Z² is selected from the groupconsisting of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OC(S)OR³,—CHR²OC(O)SR³, CHR²OCO₂R³, —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(CCR²)OH, and —CH₂NHaryl.

Class (3) prodrugs readily undergo P450 oxidation because Z² contains ahydroxyl or hydroxyl equivalent (e.g., —CHR²OC(O)R³, —CHR²N₃) with anadjacent (geminal) acidic proton. Z² groups may also readily undergoP450 oxidation because they have a benzylic methine proton or equivalent(e.g., —CH₂aryl, —CH(CH═CR² ₂)OH). Where Z² is —SR², it is believed thatthis is oxidized to the sulfoxide or sulfone which will enhance thebeta-elimination step. Where Z² is -CH₂NHaryl, the carbon next tonitrogen is oxidized to produce a hemiaminal, which hydrolizes to thealdehyde (—C(O)H), as shown above for class (3). Because V², W², and W″are not at the oxidation site in this class of prodrugs, a broad rangeof V², W², and W″ substituents is possible.

The Class (3) mechanism depicted above generally describes the oxidatonmechanism for cyclic 1,3-propanyl esters wherein together V² and Z² areconnected via an additional 3-5 atoms to form a cylic group containing5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy,alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon that isthree atoms from both Y groups attached to the phosphorus. This class ofprodrugs undergoes P450 oxidation and oxidizes by a mechanism analogousto those of class (3) described above. The broad range of W′ and Wgroups are suitable.

The mechanism of cleavage could proceed by the following mechanisms.Further evidence for these mechanisms is indicated by analysis of theby-products of cleavage. Prodrugs of class (1) depicted where Y is —O—generate phenol whereas prodrugs of class (2) depicted where Y is —O—generate phenyl vinyl ketone.

The cyclic phosphoramidates where Y is a nitrogen rather than oxygencontaining moiety can serve as a prodrug since intermediatephosphoramidates can generate the intermediate phosphonate orphosphoramidate by a similar mechanism. The phosphoramidate(—P(O)(NH₂)O⁻) is then converted to the phosphonate (—PO₃ ²).

EXAMPLES

HPLC Conditions for Example Compound Characterization

HHPLC was performed using a YMC ODS-Aq, Aq-303-5, 50×4.6 mm ID, S-5 μm,120 A column with the UV detector set at 280 or 250 nm HPLC ElutionProgram: 2.5 mL/min flow rate Time (min) % Acetonitrile (A) % Buffer^(a)(B) 0.0 0 100 6.0 100 0 6.1 0 100 8.0 0 100^(a)Buffer = 95:5:0.1 water:methanol:acetic acid

Example 1

Preparation of 5-(3,5-Dinitrophenyl)-2-furanphosphonic Acid (Compoundno. 1.01).

Step A. A solution of furan (1 mmole) in 1 mL diethyl ether was treatedwith N,N,N′N′-tetramethylethylenediamine (TMEDA) (1 mmole) and nBuLi(1.1 mmole) at −78° C. for 0.5 h. The resulting solution was cannulatedinto a solution of diethyl chlorophosphate (1.33 mmole) in 1 mL ofdiethyl ether at −60° C. and the reaction mixture allowed to rise to rtand stirred for another 16 h. Extraction and distillation at 75° C./0.2mm produced diethyl 2-furanphosphonate as a clear oil.

Step B. A solution of diethyl 2-furanphosphonate (1 mmol) in 2 mL THFwas cooled to −78° C. and added to a solution of lithiumdiisopropylamide (LDA) (1 mmol) in 5 mL THF at −78° C. over 20 min. Theresulting mixture was stirred −78° C. for 20 min and added into asolution of tributyltin chloride (1 mmole) in 1 mL TEF at −78° C. over20 min. The mixture was then stirred at −78° C. for 15 min, and at 25°C. for 1 h. Extraction and chromatography gave diethyl5-tributylstannyl-2-furanphosphonate as a colorless oil.

Step C. A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1mmol), 1-iodo-2,4-dinitrobenzene (1 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.05 mmol) in 6 mL of dioxanewas heated at 80° C. for 16 h. Evaporation of solvent and chromatographyprovided diethyl 5-(3,5-dinitrophenyl)-2-furanphosphonate as solid foam.

Step D. A mixture of diethyl 5-(3,5-dinitrophenyl)-2-furanphosphonate (1mmol) and TMSBr (6 mmol) in 10 mL of CH₂Cl₂ was stirred at rt for 16 hand then evaporated. The residue was dissolved in 85/15 CH₃CN/water andthen the solvent evaporated. The residue was suspended in CH₂Cl₂ and thetitle compound (no. 1.01) was collected as a pale yellow solid: HPLCR_(t)−5.30 min; negative ion electrospray MS M-1 found: 313. Thefollowing reagents were coupled with diethyl5-tributylstannyl-2-furanphosphonate and converted into the respectiveexample compounds (noted in parentheses) by using Steps C and D asdescribed in Example 1: 2-bromo-4,6-dinitroaniline (for 1.02);chloro-2-iodoanisole (for 1.03); 2,5-dichloro-1-iodobenzene (for 1.04);N1-methyl-2-iodo-4-(trifluoromethyl)benzene-1-sulfonamide (for 1.05);N1-methyl-4-chloro-2-iodobenzene-1-sulfonamide (for 1.06);N1-methyl-2-iodobenzene-1-sulfonamide (for 1.07);N1-propyl-4-chloro-2-iodobenzene-1-sulfonamide (for (1.08); 2-iodophenol(for 1.09); 5-iodo-m-xylene (for 1.10), 1-bromo-3-iodobenzene (for1.11); 4-iodoaniline (for 1.12); 2,5-dimethoxy-4-iodochlorobenzene (for1.13); N1-(4-chlorobenzyl)-2-iodobenzamide (for 1.14);N1-(4-chlorophenethyl)-2-iodobenzamide (for 1.15);N1-benzyl-2-iodobenzene-1-sulfonamide (for 1.16);2-iodobenzenesulfonamide (for 1.17); I-iodo-2,3,4,5,6-pentamethylbenzene(for 1.18); 3-iodophthalic acid (iodoethane and diisopropylarnineincluded in Step C, for 1.19); 4-iodo-2-methylacetanilide (for 1.20);3,5-dichloro-2-iodotoluene (for 1.21); methyl 5-hydroxy-2-iodobenzoate(for 1.22); 2-iodo-5-methylbenzamide (for 1.23); 5-hydroxy-2-iodobenzoicacid (iodoethane and diusopropylamine included in Step C, for 1.24);1-iodo-4-nitrobenzene (for 1.25);N1-(2,4-difluorophenyl)-2-iodobenzamide (for 1.26);3,5-dichloro-1-iodobenzene (1.27); 3-iodophenol (for 1.28);3-bromo-5-iodobenzoic acid (for 1.29); 3-bromo-4,5-dimethoxybenzaldehyde(for 1.30); 1-iodo-2-nitrobenzene (for 1.31);. 2-iodobiphenyl (for1.32); 2-iodobenzoic acid (iodoethane and diisopropylamine included inStep C, for 1.33); 1-bromo-4-iodobenzene (for 1.34);3′-bromopropiophenone (for 1.35); 3-bromo-4-methoxybenzonitrile (for1.36); 1-ethyl-2-iodobenzene (for 1.37); 2-bromo-3-nitrotoluene (for1.38); 4-iodoacetanilide (for 1.39); 2,3,4,5-tetramethyliodobenzene (for1.40); 3-bromobiphenyl (for 1.41); 4-chloro-2-iodobenzenesulfonamide(for 1.42); N1-(4-iodophenyl)-2-tetrahydro-1H-pyrrol-1-ylacetamide (for1.43); 3,4-dimethyliodobenzene (for 1.44); 2,4-dinitroiodobenzene (for1.45); 3-iodobenzylamine (for 1.46); 2-fluoro-4-iodoaniline (for 1.47);3-iodobenzyl alcohol (for 1.48); 2-bromo-1-iodobenzene (for 1.49);2-bromophenethyl alcohol (for 1.50); 4-iodobenzamide (for 1.51);4-bromobenzonitrile (for 1.52); 3-bromobenzonitrile (for 1.53);2-bromobenzonitrile (for 1.54); 4-bromo-2-nitroaniline (for 1.55);2-iodoisopropylbenzene (for 1.56); 6-amino-2-chloro-3-bromopyridine(derived from reaction of 6-amino-2-chlorobenzene (1 mmol) with bromine(1 mmol) in acetic acid (4 mL) for 2h at rt. followed by evaporation andchromatography to provide 6-amino-2-chloro-3-bromopyridine) (for 1.57);3-bromo-4-methylthiophene (for 1.58); 2-bromo-4-chloroaniline (for1.59); 1-bromo-3-chloro-5-fluoroaniline (for 1.60);2-bromo-4-cyanoanisole (for 1.61); 2-bromo-4-nitrotoluene (for 1.62);3-nitro-5-fluoro-1-iodobenzene (for 1.63); 2-iodo-4-carbomethoxyaniline(for 1.64); 2-bromo-4-nitroanisole (for 1.65);2-chloro-1-iodo-5-trifluoromethylbenzene (for 1.66) and1-bromo-2,5-bis-(trifluoromethyl)benzene (for 1.67).

Example 2

Preparation of 5-(4-Fluorophenyl)-2-furanphosphonic Acid (Compoundno.2.01).

Step A. A solution of diethyl 2-furanphosphonate (prepared as describedin Step A, Example 1) (1 mmol) in 2 mL THF was cooled to −78° C. andadded to a solution of lithium isopropylcyclohexylamide (LICA) (1 mmol)in 2 mL THF at −78° C. over 20 min. The resulting mixture was stirred−78° C. for 20 min and added into a solution of iodine (1 mmole) in 1 mLTIF at −78° C. over 20 min. The mixture was then stirred at −78° C. for20 min. Extraction and chromatography provided diethyl5-iodo-2-furanphosphonate as a yellow oil.

Step B. A mixture of diethyl 5-iodo-2-furanphosphonate (1 mmol),4-fluorophenylboronic acid (2 mmol), diisopropylethylamine (DIEA) (4mmol) and bis(acetonitrile)dichloropalladium(II) (0.05 mmol) in 6 mL DMFwas heated at 75° C. for 16 h. Extraction and chromatography provideddiethyl 5-(4-fluorophenyl)-2-furanphosphonate as an oil.

Step C. Application of Step D, Example 1, to this material provided thetitle compound (no. 2.01) as a white solid. HPLC R_(t)=5.09 min;negative ion electrospray MS M-1 found: 241.

Substitution of 2,4-dichlorophenylboronic acid into this method providedcompound no. 2.02. Substitution of 3-amino-5-carbomethoxyphenylboronicacid into this method provided compound no. 2.03.

Example 3

Preparation of 5-(4-Bromo-3-aminophenyl)-2-furanphosphonic Acid(Compound no. 3.01).

Step A. Reaction of 3-aminophenylboronic acid hydrochloride with diethyl5-iodo-2-furanphosphonate as described in Step B of Example 2 provideddiethyl 5-(3-aminophenyl)-2-furanphosphonate as an oil.

Step B. A mixture of diethyl 5-(3-aminophenyl)-2-furanphosphonate (1mmol), NBS (0.9 mmol) and AIBN (0.1 mmol) in 30 mL of CCl₄ was stirredat rt for 2 h. Extraction and chromatography provided diethyl5-(4-bromo-3-aminophenyl)-2-furanphosphonate as an oil.

Step C. Application of Step D, Example 1, to this material provided thetitle compound no. 3.01) as a white solid. HPLC R_(t)=4.72 min; negativeion electrospray MS M-1 found: 316/318.

Example 4

Preparation of 5-(3-(furfurylaminomethyl)phenyl)-2-furanphosphonic Acid(Compound no. 4.01).

Step A. Reaction of 3-formylphenylboronic acid with diethyl5-iodo-2-furanphosphonate as described in Step B of Example 2 provideddiethyl 5-(3-formylphenyl)-2-furanphosphonate as an oil.

Step B. A mixture of diethyl 5-(3-formylphenyl)-2-furanphosphonate (1mmol), furfurylamine (4 mmol), trimethylorthoformate (5 mmol), aceticacid (2 mmol) in 10 mL DMSO was stirred at rt for 5 h and then NaBH₄ (6mmol) was added and stirring continued for a further 16 h. The solventswere evaporated and the crude product mixture containing diethyl5-(3-(furfurylaminomethyl)phenyl)-2-furanphosphonate was used directlyin the next step.

Step C. The product mixture from Step B and TMSBr (6 mmol) in 10 mL of(CH₂Cl₂ was stirred at rt for 16 hand then evaporated. The residue wasdissolved in 85/15 CH₃CN/water and then the solvent evaporated. Themixture was dissolved in methanol with diisopropylethylamine (2 mmol)and mixed with DOWEX® IX8-400 formate resin for 1 h and then the mixturefiltered. The resin was slurried for 15 min each with 9:1 DMSO/water,methanol, acetonitrile and 85:15 acetonitrile/water. Then the resin wasmixed with 90:10 TFA/water for 1 h and then filtered this filtrate wasevaporated to provide the title compound no. 4.01) as a solid. HPLCR_(t)=4.10 min; negative ion electrospray MS M-1 found: 332.

In a similar manner the aldehydes: 3-formylphenylboronic acid,2-methoxy-5-formylphenylboronic acid, 2-formylthiophene-3-boronic acid,2-formylfuran-5-boronic acid, 2-formylphenylboronic acid and2-formyl-4-methoxyphenylboronic acid were used to prepare the followingcompounds with respective amines indicated in parentheses: 4.02, 4.03and 4.04 (furfurylamine); 4.05, 4.06 and 4.07 (phenethylamine); 4.08,4.09, 4.10 and 4.11 (1-amino-2-propanol); 4.12 and 4.13 (n-propylamine);4.14, 4.15 and 4.16 (cyclopropylamine); 4.17, 4.18, 4.19 and 4.20(3-amino-1,2-propanediol); 4.21 and 4.22 (benzylamine); 4.23 and 4.24(1-amino-3-propanol); 4.25 (n-pentylamine); 4.26, 4.27 and 4.28(phenylpropylamine); 4.29 and 4.30 (n-hexylamine); 4.31 and 4.32(phenylbutylamine); 4.33, 4.34 and 4.35 (3-methoxypropylamine); 4.36,4.37 and 4.38 (isobutylamine); 4.39, 4.40 and 4.41((±)-2-amino-1-butanol); 4.42 (N,N-diethylethylenediamine); 4.43 and4.44 (2-(2-aminoethoxy)ethanol) and 4.45 (3,3-dimethylbutylamine); 4.46and 4.47 (aniline); 4.48 (4-aminophenol); 4.49(BOC-1,4-phenylenediamine, after reductive amination the BOC group wasremoved with 90/10 TFA/water), 4.50 (acetyl-1,4-phenylenediamine), 4.51(BOC-1,4-phenylenediamine, after reductive amination the isolatedproduct was treated with acetic anhydride and then the BOC group wasremoved with 90/10 TFA/water), 4.52 (ethoxyethylamine), 4.53(5-aminobenzotriazole), 4.54 and 4.55 (3,4-methylenedioxyaniline) and4.56 (3,4,5-trimethoxyaniline).

Example 5

Preparation of5-(N-(2-(2-Hydroxyethyl)phenyl)thiophene-2-carboxamide-3-yl)furanphosphonicAcid (Compound no. 5.01).

Step A. A solution of 3-bromothiophene-2-carboxylic acid (1 mmol) andSOCl₂ (3 mmol) in 1 mL of dichloroethane was heated at 80° C. for 20 hand then the solvents evaporated. The residue was dissolved in 2 mLCH₂Cl₂ and mixed with triethylamine (3 mmol) and2-(trimethylsilyl)ethanol (1.3 mmol) at rt for 12 h. Extractiveisolation provided 2-(trimethylsilyl)ethyl3-bromo-2-thiophenecarboxylate as an oil.

Step B. A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1mmol) and 2-(trimethylsilyl)ethyl 3-bromo-2-thiophenecarboxylate (1.2mmol) were coupled as described in Step C of Example 1 to providediethyl5-(2-(carbo(2-trimethylsilylethoxy))-3-thienyl)-2-furanphosphonate as anoil.

Step C. A solution of diethyl5-(2-(carbo(2-trimethylsilylethoxy))-3-thienyl)-2-furanphosphonate (1mmol) and tetrabutylammonium fluoride (1.5 mmol) in 6 mL of THF wasstirred at rt for 16 h. Extractive isolation provided diethyl5-(2-carboxy-3-thienyl)-2-furanphosphonate as an oil.

Step D. A mixture of diethyl 5-(2-carboxy-3-thienyl)-2-furanphosphonate(1 mmol), 2-(2-hydroxyethyl)aniline (1.5 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.5mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (1.5 mmol) in 8 mL ofDMF was stirred for 16 h at rt. Extraction and chromatography provideddiethyl5-(N-(2-(2-hydroxyethyl)phenyl)thiophene-2-carboxamide-3-yl)furanphosphonateas an oil.

Step E. Diethyl5-(N-(2-(2-hydroxyethyl)phenyl)thiophene-2-carboxamide-3-yl)furanphosphonatewas deesterified with TMSBr as described in Step D, Example 1, toprovide the title compound (no. 5.01) as a solid. HPLC R_(t)=5.17 mm;negative ion electrospray MS M-1 found: 392.

In a similar manner the carboxylic acids: 2-iodobenzoic acid,3-iodobenzoic acid, 4-iodobenzoic acid, 3-bromothiophene-2-carboxylicacid, 5-bromo-2-furoic acid, 3-bromothiophene-2-carboxylic acid,5-bromothiophene-2-carboxylic acid and 5-bromonicotinic acid were usedto prepare the following compounds with respective amines indicated inparentheses: 5.02 (N-methylfurfurylamine); 5.03, 5.04, 5.05(2-(2-hydroxyethyl)aniline); 5.06 and 5.07 (3-hydroxymethylaniline);5.08 (8-aminoquinoline); 5.09 and 5.10 (3-aminoquinoline); 5.11(3-aminobenzamide); 5.12, 5.13 (4-aminophenol); 5.14 and 5.15(3,4-methylenedioxyaniline); 5.16 (4-aminobenzamide); 5.17(cyclopropylamine); 5.18 (t-butylamine); 5.19, 5.20(3,3-dimethylbutylamine); 5.21. (n-pentylamine); 5.22 and 5.23(n-hexylamine); 5.24 (benzylamine); 5.25, 5.26 (phenethylamine); 5.27and 5.28 (phenpropylamine); 5.29 and 5.30 (phenbutylamine); 5.31 and5.32 (ethanolamine); 5.33 (2-(2-aminoethoxy)ethanol); 5.34(3-ethoxypropylamine); 5.35, 5.36 and 5.37 (ethylenediamine mono-bocamide); 5.38, 5.39 4-(2-aminoethyl)morpholine); 5.40, 5.41 and 5.42(piperonylamine); 5.43, 5.44, 5.45, 5.46, 5.47 and 5.48(tetrahydrofurfurylamine); 5.49 and 5.50 (cyclohexylamine); 5.51(2-aminoacetamide); 5.52 (6-methyl-2-picolylmethylamine) and 5.53(morpholine).

Example 6

Preparation of1-(3-Bromophenylcarbamoyl)-3-carboethoxy-6-(2-phosphonofuran-5-yl)benzene(Compound no. 6.01).

Step A. A mixture of 3-carboxy-5-nitrophenylboronic acid (1 mmol),diethyl 5-iodo-2-furanphosphonate (1.5 mmol) andtetrakistriphenylphosphinepalladium(0) (0.05 mmol) were dissolved in 1.5mL of 1,4-dioxane and 0.25 mL of DMF. After bubbling N₂ into thissolution for 5 min then 1.5 mL of I M aqueous K₃PO₄ were added. After N₂bubbling for 5 min the mixture was heated at 85° C. for 14 h and thencooled and diluted with EtOAc and water. The layers were separated, theEtOAc layer extracted with water. The aqueous layers were combined, pHlowered to pH 2 and then extracted with EtOAc. The EtOAc extract wasdried (MgSO₄) and evaporated. Chromatography on silica gel provided1-nitro-3-carboxy-5-(diethyl 2-phosphonofuran-5-yl)benzene.

Step B. A mixture of 1-nitro-3-carboxy-5-(diethyl2-phosphonofuran-5-yl)benzene (1 mmol), trimethylsilylethanol (1 mmol),EDCI (1.1 mmol) and DMAP (0.1 mmol) were stirred in 2 mL of CH₂Cl₂ at rtfor 16 h. Extractive isolation provided1-nitro-3-carbotrimethylsilylethoxy-5-(diethyl2-phosphonofuran-5-yl)benzene.

Step C. A mixture of 1-nitro-3-carbotrimethylsilylethoxy-5-(diethyl2-phosphonofuran-5-yl)benzene (1 mmol) and 10% Pd/C (80 mg) in 10 mL ofEtOAc and 5 mL of MeOH was stirred at rt under an atmosphere of hydrogenfor 6 h. The mixture was filtered over Celite and purified by silica gelchromatography to provide 1-amino-3-carbotrimethylsilylethoxy-5-(diethyl2-phosphonofuran-5-yl)benzene.

Step D. A mixture of 1-amino-3-carbotrimethylsilylethoxy-5-(diethyl2-phosphonofuran-5-yl)benzene (1 mmol), 3-bromobenzoyl chloride (4 mmol)and triethylamine (4.5 mmol) in 30 mL of CH₂Cl₂ was stirred at rt for 4h. Then 5 mL of water was added and after stirring for 30 min themixture was evaporated. The residue was dissolved in MeOH and slurriedwith 5 g of DOWEX 1X8-400 carbonate resin. The mixture was filtered andthe solvent evaporated to provide1-(3-bromophenylcarbamoyl)-3-carbotrimethylsilylethoxy-5-(diethyl2-phosphonofuran-5-yl)benzene.

Step E. A mixture of1-(3-bromophenylcarbamoyl)-3-carbotrimethylsilylethoxy-5-(diethyl2-phosphonofuran-5-yl)benzene (1 mmol) and 4.5 mL of a 1 M solution ofBu₄NF in THF were stirred in 10 mL of THF for 6 h at rt. To this mixturewas added 5 grams of DOWEX 50WX8-400 free acid and 5 grams of DOWEX50WX8-400 sodium salt. After slurrying this mixture for 14 h the mixturewas filtered and the filtrate evaporated to provide1-(3-bromophenylcarbamoyl)-3-carboxy-5-(diethyl2-phosphonofuran-5-yl)benzene.

Step F. A mixture of 1-(3-bromophenylcarbamoyl)-3-carboxy-5-(diethyl2-phosphonofuran-5-yl)benzene (1 mmol), EDCI (2 mmol), DMAP (0.1 mmol)and ethanol (1.5 mmol) in 70 mL of CH₂Cl₂ were stirred at rt for 14 h.After evaporation the mixture was redissolved in MeOH and slurried with5 g of DOWEX 50WX8-400 free acid and 5 g of DOWEX 1X8-400 bicarbonateresin for 4 h and then filtered. The filtrate was evaporated to provide1-(3-bromophenylcarbamoyl)-3-carboethoxy-5-(diethyl2-phosphonofuran-5-yl)benzene.

Step G. Application of Step D, Example 1, to this material provided thetitle compound (no. 6.01) as a white solid. HPLC R_(t)=6.58 min;negative ion electrospray MS M-1 found: 492/494.

In a similar manner, the following compounds were prepared: 6.02, 6.03,6.04 and 6.05.

Example 7

Preparation of 2-Methyl-4-isobutyl-5-[2-(5-phosphono)furanyl]oxazole(Compound no. 7.01).

Step A. A solution of 5-diethylphosphono-2-[(4-methyl-1-oxo)pentyl]furan(1 mmole) and cupric bromide (3.5 mmole) in ethanol was refluxed for 2h. The reaction mixture was cooled to room temperature, then filtered.Evaporation and chromatography gave5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan.

Step B. A solution of5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmole) inacetic acid was treated with sodium acetate (2 mmole) and ammoniumacetate (2 mmole) at 100° C. for 4 h. Evaporation and chromatographygave 2-methyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]oxazole as anoil.

Step C. The compound2-methyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]oxazole wasdeesterified with TMSBr as described in Step D, Example 1, to providethe title compound (no. 7.01) as a solid. HPLC R_(t)=5.04 min; negativeion electrospray MS M-1 found: 284.

Example 8

Preparation of N-(Phosphonomethyl)-5-bromofuran-2-carboxamide (Compoundno.8.01).

5-Bromofuroic acid was reacted with diethyl aminomethylphosphonate in amanner similar to that described in Step D, Example 5. The product wastreated with TMSBr as described in Step D, Example 1 to provide thetitle compound (no. 8.01) as a solid. BPLC R_(t)=3.72 min; negative ionelectrospray MS M-1 found: 282/284.

This method was used with the following reagents to prepare therespective compounds (in parentheses): 3-bromobenzoic acid (for 8.02);3-bromo-4-methoxybenzoic acid (for 8.03); 3,5-dibromobenzoic acid (for8.04); 5-bromo-2-chlorobenzoic acid (for 8.05);3,5-dichloro-2-hydroxybenzoic acid (for 8.06); 4-bromobenzoic acid (for8.07); 4-toluic acid (for 8.08); 4-bromo-2-methylbenzoic acid (for8.09); 4-iodobenzoic acid (for 8.10); 3-furoic acid (for 8.11);5-bromothiophene-2-carboxylic acid (for 8.12), 3-iodobenzoic acid (for8.13) and 3,5-dinitrobenzoic acid (for 8.14).

Example 9

Preparation of N-(Diethylphosphonomethyl)-2-amino-3-chlorobenzamide(Compound no. 9.01).

Step A. To a solution of 3-chloro-2-nitrobenzoic acid (1 mmol) andaminomethylenediethyl phosphonate (1.1 mmol) in dichloromethane (5 mL)was added diisopropylethylamine (5 mmol) followed by pyBOP (1.5 mmol).The reaction was stirred at room temperature for 3 h and concentrated.The mixture was purified by chromatography to yieldN-(diethylphosphonomethyl)-2-nitro-3-chlorobenzamide as a solid.

Step B. To a solution ofN-(diethylphosphonomethyl)-2-nitro-3-chlorobenzamide (1 mmol) inmethanol (10 mL) was added sodiumdithionite (3 mmol) and the mixturestirred for 1 h and concentrated. The mixture was extracted andchromatographed to result inN-(diethylphosphonomethyl)-2-amino-3-chlorobenzamide.

Step C. The compoundN-(diethylphosphonomethyl)-2-amino-3-chlorobenzamide was deesterifiedwith TMSBr as described in Step D, Example 1, to provide the titlecompound (no. 9.01) as a solid. HPLC R_(t)=4.48 min; negative ionelectrospray MS M-1 found: 263.

Example 10

Preparation of N-(4-Bromophenyl)phosphonomethylcarboxamide (Compound no.10.01).

4-Bromoaniline was reacted with diethylphosphonoacetic acid in a mannersimilar to that described in Step D, Example 5. The product was treatedwith TMSBr as described in Step D, Example 1 to provide the titlecompound (no. 10.01) as a solid. HPLC R_(t)=4.91 min; negative ionelectrospray MS M-1 found: 292/294.

This method was used with the following reagents to prepare therespective compounds (in parentheses): 2-hydroxy-5-nitroaniline (for10.02); 2-hydroxyaniline (for 10.03); 3,5-dichloroaniline (for 10.04);3,5-dimethylaniline (for 10.05); 3-chloro-4-methylaniline (for 10.06);3-chloroaniline (for 10.07); 3-iodoaniline (for 10.08);4,5-dichloro-1,2-phenylenediamine (for 10.09); 4-chloroaniline (for10.10); 4-fluoroaniline (for 10.11) and 4-iodoaniline (for 10.12).

Example 11

Preparation of Phosphonomethyl 4-Chloro-2-methoxybenzoate (Compound no.11.01).

Step A. A mixture of 4-chloro-2-methoxybenzoic acid (1 mmol), oxalylchloride (1 mmol), and DMF (0.05 mmol) in 2 mL of CH₂Cl₂ was stirred atrt for 6 h and then evaporated. To the residue was added 2 mL of CH₂Cl₂,triethylamine (2 mmol) and diethyl (hydroxymethyl)phosphonate (0.33mmol) and this mixture was stirred at rt for 16 h and then diluted withwater and CH₂Cl₂. The organic layer was dried (MgSO₄) and evaporated.Purification of the residue by silica gel chromatography provideddiethylphosphonomethyl 4-chloro-2-methoxybenzoate as an oil.

Step B. This compound was deesterified with TMSBr as described in StepD, Example 1, to provide the title compound (no. 11.01) as a solid. HPLCR_(t)=5.21 min; negative ion electrospray MS M-1 found: 279.

The following compounds were prepared in the same manner from theirrespective carboxylic acids indicated in parentheses: 11.02(5-bromo-2-furoic acid); 11.03 (3-toluic acid); 11.04 (4-fluorobenzoicacid); 11.05 (5-chloro-2-methoxybenzoic acid); 11.06(2-biphenylcarboxylic acid); 11.07 (3-bromo-5-carboxypyridine) and 11.08(2,6-dichloronicotinic acid).

Example 12

Preparation of Phosphonomethyl 3-Bromo-2-methoxybenzoate (Compoundno.12.01)

Step A. A mixture of diethyl (hydroxymethyl)phosphonate (1.2 mmol),2-anisoyl chloride (1 mmol) and pyridine (2 mmol) in 5 mL CH₂Cl₂ werestirred at rt for 4 h. Extraction and chromatography provideddiethylphosphonomethyl 2-methoxybenzoate as an oil.

Step B. A mixture of diethylphosphonomethyl 2-methoxybenzoate (1 mmol)and bromine (100 mmol) in 10 mL CHCl₃ was stirred at rt for 16 h.Extraction and chromatography provided diethylphosphonomethyl3-bromo-2-methoxybenzoate as an oil.

Step C. This compound was deesterified with TMSBr as described in StepD, Example 1, to provide the title compound (no. 12.01) as a solid. HPLCR_(t)=4.93 min; negative ion electrospray MS M-1 found: 323/325.

Example 13

Preparation of 4-Bromo-3-methoxyphenylmethoxymethylphosphonic acid(Compound no. 13.01).

Step A. A mixture of 3-methoxybenzyl alcohol (1 mmol) and sodium hydride(1.5 mmol) in 5 mL DMF was stirred at rt for 1 h and then added viacannula to a solution of diethylphosphonomethyl triflate (1 mmol) in 5mL of DMF and the resulting mixture stirred at rt for 16 h. Extractionand chromatography provided diethyl3-methoxyphenylmethoxymethylphosphonate as an oil.

Step B. Reaction of diethyl 3-methoxyphenylmethoxymethylphosphonate andbromine as described in Step 2 of Example 10 provided diethyl4-bromo-3-methoxyphenylmethoxymethylphosphonate as an oil.

Step C. This compound was deesterified with TMSBr as described in StepD, Example 1, to provide the title compound (no. 187) as a solid. HPLCR_(t)=5.24 min; negative ion electrospray MS M-1 found: 309/311.

Compound 13.02 was prepared similarly from 3,5-dinitrobenzyl alcohol.

Example 14

Preparation of 2,4-Dichloro-5-(phosphonomethoxymethyl)thiazole (Compoundno. 14.01).

Step A. To a solution of 2,4-dichloro-5-(hydroxymethyl)thiazole (J.Chem. Soc. Perkin I 1992, 973) (1 mmol) in dichloromethane at 0° C. wasadded 1M phosphorus tribromide in dichloromethane (1.1 mmol) and themixture allowed to stir at rt for 1 h. The product2,4-dichloro-5-(bromomethyl)thiazole was extracted and purified bycolumn chromatography.

Step B. To a solution of diethyl hydroxymethylphosphonate (1.2 mmol) inTHF (10 mL) at 0° C. was added 60% sodium hydride (1.1 mrnol) andallowed to stir for 15 minutes before adding2,4-dichloro-5-(bromomethyl)thiazole (1 mmol). The mixture was warmed toroom temperature and allowed to stir for 3 h. The reaction was extractedand chromatographed to yield2,4-dichloro-5-(diethylphosphonomethoxymethyl)thiazole.

Step C. 2,4-Dichloro-5-(diethylphosphonomethoxymethyl)thiazole wasdeesterified with TMSBr as described in Step D, Example 1, to providethe title compound (no. 14.01) as a solid. HPLC R_(t)=4.36 min; negativeion electrospray MS M-1 found: 276/278.

Example 15

Preparation of 2-Amino-4-tert-butyl-1-phosphonomethoxybenzene (Compoundno. 15.01).

Step A. A solution of 2-amino-4-tert-butylphenol (1 mmole) in DMF wastreated with sodium hydride (1.2 mmole) and trifluoromethanesulfonicacid 2-diethylphosphonomethyl ester (1.2 mmole) at room temperature for6 h. Evaporation and chromatography gave2-amino-4-tert-butyl-1-diethylphosphonomethoxybenzene as an oil.

Step B. The compound2-amino-4-tert-butyl-1-diethylphosphonomethoxybenzene was deesterifiedwith TMSBr as described in Step D, Example 1, to provide the titlecompound (no. 15.01) as a solid. HPLC R_(t)=4.45 min; negative ionelectrospray MS M-1 found: 258.

Example 16

Preparation of 1-Phosphono-2-phenylacetylene (Compound no. 16.01).

Step A. A solution of iodobenzene (1 mmole) in DME (5 mL) was treatedwith trimethylsilylacetylene (2 mmole), Pd(PPh₃)₂Cl₂ (0.035 mmole), CuI(0.08 mmole) and triethylamine (4 mmole), and the resulting reactionmixture was stirred under nitrogen at room temperature for 5 h.Evaporation followed by chromatography gave1-trimethylsilyl-2-phenylacetylene as a solid.

Step B. A solution of 1-trimethylsilyl-2-phenylacetylene (1 mmole) inanhydrous THF (5 mL) was treated with a solution of tetrabutylammoniumfluoride (1.5 mmole) at 0° C. for 1 h. Extraction and chromatographygave phenylacetylene.

Step C. A solution of phenylacetylene (1 mmole) in anhydrous THF (5 mL)was treated with TMEDA (1.2 mmole) followed by n-BuLi (1.2 mmole) at−78° C. After 30 min the reaction was treated with diethylchlorophosphate, and the resulting solution was stirred at −78° C. for 1h. The reaction was quenched with saturated ammonium chloride.Extraction and chromatography gave 1-diethylphosphono-2-phenylacetyleneas an oil.

Step D. 1-Diethylphosphono-2-phenylacetylene was deesterified with TMSBras described in Step D, Example 1, to provide the title compound (no.16.01) as a solid. HPLC R_(t)=3.75 min; negative ion electrospray MS M-1found: 181.

Example 17

General Procedure for Preparation of Bis-Phosphoroamide Prodrugs.

Step A. Dichloridate formation. To a suspension of 1 mmol of phosphonicacid in 5 mL of dichloroethane is added 0.1 mmol of pyridine (or 0.1mmol of DMF) followed by 6 mmol of thionyl chloride and it is heated toreflux for 2.5 h. Solvent and excess thionyl chloride are removed underreduced pressure and dried to give the dichloridate.

Step B. Coupling, reaction.

Method 1: To a solution of the crude dichloridate in 5 mL of dry CH₂Cl₂is added 8 mmol of aminoacid ester at 0° C. The resultant mixture isallowed to come to rt where it is stirred for 16 h. The reaction mixtureis subjected to extractive work up and chromatography to provide thetar-et bisphosphoramide.

Method 2: To the crude dichloridate in 5 mL of dry CH₂Cl₂ is added 4mmol of aminoacid ester and 4 mmol of N-methylimidazole at 0° C. Theresultant mixture is allowed to come to rt where it is stirred for 16 h.The reaction mixture is subjected to extractive work up andchromatography to provide the target bisphosphoramide.

Example 18

General Procedure for Mixed Bis-Phosphoroamidate Prodrugs.

To a solution of crude dichloridate (1 mmol, prepared as described inStep A in Example 15) in 5 mL of dry CH₂Cl₂ is added an amine (1 mmol)followed by 4-dimethylaminopyridine (3 mmol) at 0° C. The resultingmixture is allowed to warm to room temperature and stir for I h. Thereaction is cooled back to 0° C. before adding an amino acid ester (2mmol) and then is left at room temperature for 16 h. The reactionmixture is subjected to extractive work up and the mixedbis-phosphoroamidate prodrug is purified by column chromatography.

BIOLOGICAL EXAMPLES Example A Inhibition of Human Liver FBPase

E. coli strain BL21 transformed with a human liver FBPase-encodingplasmid was obtained from Dr. M. R. El-Maghrabi at the State Universityof New York at Stony Brook. The enzyme was typically purified from 10liters of recombinant E. coli culture as described (M. Gidh-Jain et al.,1994, The Journal of Biological Chemistry 269, pp 27732-27738).Enzymatic activity was measured spectrophotometrically in reactions thatcoupled the formation of product (fructose-6-phosphate) to the reductionof dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP⁺ andphenazine methosulfate (PMS), using phosphoglucose isomerase and glucose6-phosphate dehydrogenase as the coupling enzymes. Reaction mixtures(200 μl) were made up in 96-well microtitre plates, and consisted of 50mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl₂, 0.2 mM NADP, 1mg/ml BSA, 1 mM MTT, 0.6 mM PMS, 1 unit/ml phosphoglucose isomerase, 2units/ml glucose 6-phosphate dehydrogenase, and 0.150 mM substrate(fructose-1,6-bisphosphate). Inhibitor concentrations were varied from0.01 μM to 10 μM. Reactions were started by the addition of 0.002 unitsof pure hlFBPase, and were monitored for 7 minutes at 590 nm in aMolecular Devices Plate Reader (37° C.).

Table 3 below provides the IC₅₀ values for several compounds prepared.The IC₅₀ for AMP is 1 μM. TABLE 3 Human Liver Compound No. FBPase IC₅₀(μM) 1.01 0.31 1.02 1.8 1.03 0.50 2.01 2.2 2.02 3 2.03 2.6 3.01 5.5 4.463 4.48 0.14 4.49 0.32 4.50 6.5 4.51 12 8.01 4 8.14 4 9.01 60 11.01 2.811.02 6.4 12.01 4.2 13.01 11 13.02 9 16.01 89Inhibition of Rat Liver FBPase

E. coli strain BL21 transformed with a rat liver FBPase-encoding plasmidis obtained from Dr. M. R. El-Maghrabi at the State University of NewYork at Stony Brook. Recombinant FBPase is purified as described(El-Maghrabi, M. R., and Pilkis, S. J. (1991) Biochem. Biophys. Res.Commun. 176, 137-144) The enzyme assay is identical to that describedabove for human liver FBPase. The IC₅₀ for AMP is 20 μM.

Example B AMP Site Binding

To assess whether compounds bind to the allosteric AMP binding site ofhlFBPase, the enzyme is incubated with radio-labeled AIMP in thepresence of a range of test compound concentrations. The reactionmixtures consist of 25 mM ³H-AMP (54 mCi/mmole) and 0-1000 mM testcompound in 25 mM Tris-HCl, pH 7.4, 100 mM KCl and 1 mM MgCl₂. 1.45 mgof homogeneous FBPase (±1 nmole) is added last. After a 1 minuteincubation, AMP bound to FBPase is separated from unbound AMP by meansof a centrifugal ultrafiltration unit (“Ultrafree-MC”, Millipore) usedaccording to the instructions of the manufacturer. The radioactivity inaliquots (100 μl) of the upper compartment of the unit (the retentate,which contains enzyme and label) and the lower compartment (thefiltrate, which contains unbound label) is quantified using a Beckmanliquid scintillation counter. The amount of AMP bound to the enzyme isestimated by comparing the counts in the filtrate (the unbound label) tothe total counts in the retentate.

Example C AMP Site/Enzyme Selectivity

To determine the selectivity of compounds towards FBPase, effects ofFBPase inhibitors on 5 key AMP binding enzymes is measured using theassays described below:

-   -   Adenosine Kinase: Human adenosine kinase is purified from an E.        coli expression system as described by Spychala et al.        (Spychala, J., Datta, N. S., Takabayashi, K., Datta, M., Fox, I.        H., Gribbin, T., and Mitchell, B. S. (1996) Proc. Natl. Acad.        Sci. USA 93, 1232-1237). Activity was measured essentially as        described by Yamada et al. (Yamada, Y., Goto, H.,        Ogasawara, N. (1988) Biochim. Biophys. Acta 660, 36-43.) with a        few minor modifications. Assay mixtures contain 50 mM        TRIS-maleate buffer, pH 7.0, 0.1% BSA, 1 mM ATP 1 mM MgCl₂, 1.0        μM [U-¹⁴C] adenosine (400-600 mCi/mmol) and varying duplicate        concentrations of inhibitor. ¹⁴C-AMP was separated from        unreacted ¹⁴C-adenosine by absorption to anion exchange paper        (Whatman) and quantified by scintillation counting.    -   Adenosine Monophosphate Deaminase. Porcine heart AMPDA is        purified essentially as described by Smiley et al. (Smiley, K.        L., Jr, Berry, A. J., and Suelter, C. H. (1967) J. Biol. Chem.        242 2502-2506) through the phosphocellulose step. -Inhibition of        AMPDA activity is determined at 37° C. in a 0.1 ml assay mixture        containing inhibitor, ˜0.005U ALMPDA, 0.1% bovine serum        albuimin, 10 mM ATP, 250 mM KCl, and 50 mM MOPS at pH 6.5. The        concentration of the substrate AMP is varied from 0.125-10.0 mM.        Catalysis is initiated by the addition of enzyme to the        otherwise complete reaction mixture, and terminated after 5        minutes by injection into an HPLC system. Activities are        determined from the amount of IMP formed during 5 minutes. IMP        is separated from AMP by HPLC using a Beckman Ultrasil-SAX anion        exchange column (4.6 mm×25 cm) with an isocratic buffer system        (12.5 mM potassium phosphate, 30 mM KCl, pH 3.5) and detected        spectrophotometrically by absorbance at 254 nm.    -   Phosphofructokinase: Enzyme (rabbit liver) is purchased from        Sigma. Activity is measured at 30° C. in reactions in which the        formation of fructose-1,6-bisphosphate is coupled to the        oxidation of NADH via the action of aldolase, triosephosphate        isomerase, and α-glycerophosphate dehydrogenase. Reaction        mixtures (200 μl) are made up in 96-well microtitre plates and        were read at 340 nm in a Molecular Devices Microplate Reader.        The mixtures consist of 200 mM Tris-HCl pH 7.0, 2 mM DTT, 2 mM        MgCl₂, 0.2 mM NADH, 0.2 MM ATP, 0.5 mM Fructose 6-phosphate, 1        unit aldolase/ml, 3 units/ml triosephosphate isomerase, and 4        units/ml α-glycerophosphate dehydrogenase. Test compound        concentrations range from 1 to 500 μM. Reactions are started by        the addition of 0.0025 units of phosphofructokinase and are        monitored for 15 minutes.    -   Glycogen Phosphorylase: Enzyme (rabbit muscle) is purchased from        Sigma. Activity is measured at 37° C. in reactions in which the        formation of glucose 1-phosphate is coupled to the reduction of        NADP via phosphoglucomutase and glucose 6-phosphate        dehydrogenase. Assays are performed on 96-well microtitre plates        and are read at 340 nm on a Molecular Devices Microplate Reader.        Reaction mixtures consist of 20 mM imidazole, pH 7.4, 20 mM        MgCl₂, 150 mM potassium acetate, 5 mM potassium phosphate, 1 mM        DTT, 1 mg/ml BSA, 0.1 mM NADP, 1 unit/ml phosphoglucomutase, 1        unit/ml glucose 6-phosphate dehydrogenase, 0.5% glycogen. Test        compound concentrations range from 1 to 500 μM. Reactions are        started by the addition of 17 μg enzyme and are monitored for 20        minutes.    -   Adenylate Kinase: Enzyme (rabbit muscle) is purchase from Sigma.        Activity is measured at 37° C. in reaction mixtures (100 μl)        containing 100 mM Hepes, pH 7.4, 45 mM MgCl₂, 1 mM EGTA, 100 mM        KCl, 2 mg/ml BSA, 1 mM AMP and 2 mM ATP. Reactions are started        by addition of 4.4 ng enzyme and terminated after 5 minutes by        addition of 17 μl perchloric acid. Precipitated protein is        removed by centrifugation and the supernatant neutralized by        addition of 33 μl 3 M KOH/3 M KHCO₃. The neutralized solution is        clarified by centrifugation and filtration and analyzed for ADP        content (enzyme activity) by HPLC using a YMC ODS AQ column        (25×4.6 cm). A gradient is run from 0.1 M KH₂PO₄, pH 6, 8 mM        tetrabutyl ammonium hydrogen sulfate to 75% acetonitrile.        Absorbance is monitored at 254 nM.

Example D Inhibition of Gluconeogenesis in Rat Hepatocytes

Hepatocytes are prepared from overnight fasted Sprague-Dawley rats(250-300 g) according to the procedure of Berry and Friend (Berry, M.N., Friend, D. S., 1969, J. Cell. Biol. 43, 506-520) as modified byGroen (Groen, A. K., Sips, H. J., Vervoom, R. C., Tager, J. M. , 1982,Eur. J. Biochem. 122, 87-93). Hepatocytes (75 mg wet weight/ml) areincubated in 1 ml Krebs-bicarbonate buffer containing 10 mM Lactate, 1mM pyruyvate, 1 mg/ml BSA, and test compound concentrations from 1 to560 μM. Incubations are carried out in a 95% oxygen, 5% carbon dioxideatmosphere in closed, 50-ml Falcon tubes submerged in a rapidly shakingwater bath (37° C.). After 1 hour, an aliquot (0.25 ml) is removed,transferred to an Eppendorf tube and centrifuged. 50 μl of supernatantis then assayed for glucose content using a Sigma Glucose Oxidase kit asper the manufacturer's instructions.

Example E Glucose Production Inhibition and Fructose-1,6-bisphosphateAccumulation in Rat Hepatocytes

Isolated rat hepatocytes are prepared as described in Example D andincubated under the identical conditions described. Reactions areterminated by removing an aliquot (250 μl) of cell suspension andspinning it through a layer of oil (0.8 ml silicone/mineral oil, 4/1)into a 10% perchloric acid layer (100 μl). After removal of the oillayer, the acidic cell extract layer is neutralized by addition of ⅓rdvolume of 3 M KOH/3 M KHCO₃. After thorough mixing and centrifugation,the supernatant is analyzed for glucose content as described in ExampleD, and also for fructose-1,6-bisphosphate. Fructose-1,6-bisphosphate isassayed spectrophotometrically by coupling its enzymatic conversion toglycerol 3-phosphate to the oxidation of NADH, which is monitored at 340nm. Reaction mixtures (1 ml) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mMNADH, 2 units/ml glycerol 3-phosphate dehydrogenase, 2 units/mltriosephosphate isomerase, and 50-100 μl cell extract. After a 30 minutepreincubation at 37° C., 1 unit/ml of aldolase is. added and the changein absorbance measured until a stable value is obtained. 2 moles of NADHare oxidized in this reaction per mole of fructose-1,6-bisphosphatepresent in the cell extract.

A dose-dependent inhibition of glucose production accompanied by adose-dependent accumulation of fructose-1,6 bisphosphate (the substrateof FBPase) is an indication that the target enzyme in the gluconeogenicpathway, FBPase, is inhibited.

Example F Blood Glucose Lowering, Following Intravenous Administrationto Fasted Rats

Sprague Dawley rats (250-300 g) are fasted for 18 hours and then dosedintravenously either with saline or up to about 60 mg/kg of an FBPaseinhibitor. Inhibitors are dissolved in water and the solution adjustedto neutrality with NaOH. Blood samples are obtained from the tail veinof conscious animals just prior to injection and after 1 hour. Bloodglucose is measured using a HemoCue Inc. glucose analyzer according tothe instructions of the manufacturer.

Example G Analysis of Drug Levels and Liver Accumulation in Rats

Sprague-Dawley rats (250-300 g) are fasted for 18 hours and then dosedintravenously either with saline up to about 60 mgs/kg of a compound ofthe invention. The compound is dissolved in water and the solutionadjusted to neutrality with NaOH. One hour post injection rats areanesthetized with halothane and a liver biopsy (approx. 1 g) is taken aswell as a blood sample (2 ml) from the posterior vena cava. A heparinflushed syringe and needle are used for blood collection. The liversample is immediately homogenized in ice-cold 10% perchloric acid (3ml), centrifuged, and the supernatant neutralized with ⅓rd volume of 3 MKOH/3 M KHCO₃. Following centrifugation and filtration, 50 μl of theneutralized extract is analyzed for compound content by HPLC. A YMC ODSAQ column (250×4.6 cm) is used and eluted with a gradient from 10 mMsodium phosphate pH 5.5 to 75% acetonitrile. Absorbance is monitored at310-325 nm. Plasma is prepared from the blood sample by centrifugationand extracted by addition of methanol to 60% (v/v). The methanolicextract is clarified by centrifugation and filtration and then analyzedby HPLC as described above.

Example H Glucose Lowering Following Oral Administration to the FastedRat

Compounds are administered by oral gavage to 18-hour fasted, SpragueDawley rats (250-300 g). Phosphonic acids are prepared in deionizedwater, and the solution adjusted to neutrality with sodium hydroxide.Prodrugs are dissolved in polyethylene glycol (mw 400). Blood glucose ismeasured immediately prior to dosing and at 1 hour intervals thereafterby means of a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo,Calif.).

Example I Estimation of the Oral Bioavailability of Phosphonic Acids andTheir Prodrugs

Phosphonic acids are dissolved in water, and the solution adjusted toneutrality with sodium hydroxide. Prodrugs are dissolved in 10%ethanol90% polyethlene glycol (mw 400). Compound is administered by oralgavage to 18-hour fasted Sprague-Dawley rats (220-250 g) at dosesranging from 10-60 mg/kg. The rats are subsequently placed in metaboliccages and urine is collected for 24 hours. The quantity of phosphonicacid excreted into urine is determined by HPLC analysis as described inExample G. In a separate study, urinary recovery is determined followingintravenous (tail vein) administration of compound (in the case of theprodrugs, the appropriate parent phosphonic acid is administered I.V.).The percentage oral bioavailability is estimated by comparison of therecovery of compound in urine 24 hours following oral administration, tothat recovered in urine 24 hours after intravenous administration.

Example J Blood Glucose Lowering in Zucker Diabetic Fatty Rats, Oral

Zucker Diabetic Fatty rats are purchased from Genetics Models Inc.(Indianapolis, Ind.) at 8 weeks of age and fed the recommended Purina5008 diet. At the age of 12 weeks, 16 animals with fed blood glucoselevels between 500 and 700 mg/dl are selected and divided into twogroups (n=8) with statistically equivalent average blood glucose levels.A compound of the invention is administered at a dose of up to about 300mg/kg by oral gavage to one group of animals at 1 p.m. The drug solutionfor this treatment is prepared in deionized water and adjusted toneutrality by dropwise addition of 5 N NaOH. A second group of rats(n=8) is dosed orally with saline, in parallel. Blood glucose ismeasured in each rat just prior to drug or saline administration and 6hours post administration. A HemoCue blood glucose analyzer (HemoCueInc., Mission Viejo, Calif.) is used for these measurements according tothe manufacturer's instructions.

Example K Blood Glucose Lowering in Zucker Diabetic Fatty Rats,Intravenous

12-week old Zucker Diabetic Fatty rats (Genetics Models Inc.,Indianapolis, Ind.) maintained on Purina 5008 diet are instrumented withtail artery and tail vein catheters at 8 am on the day of the study.Food is removed for the remainder of the day. Starting at 12 p.m.,animals are infused for 6 hours via the tail vein catheter either withsaline or compound of the invention at up to about 60 mg/kg/h. Bloodsamples are obtained from the tail artery catheter at the start of theinfusions, and at hourly intervals thereafter. Glucose is measured inthe samples by means of a HemoCue analyzer (HemoCue Inc., Mission Viejo,Calif.) according to the manufacturer's instructions.

Example L Inhibition of Gluconeogenesis by FBPase Inhibitor in ZuckerDiabetic Fatty Rats

Following a 6-hour infusion of a compound of the invention at up toabout 60 mg/kg/h or saline to Zucker Diabetic Fatty rats (n=3/group) asdescribed in Example K, a bolus of ¹⁴C-bicarbonate (40 μCi/100 g bodyweight) is administered via the tail vein catheter. 20 minutes later, ablood sample (0.6 mL) is taken via the tail artery. Blood (0.5 ml) isdiluted into 6 mL deionized water and protein precipitated by additionof 1 mL zinc sulfate (0.3 N) and 1 mL barium hydroxide (0.3 N). Themixture is centrifuged (20 minutes, 1000× g) and 5 mL of the resultingsupernatant is then combined with 1 g of a mixed bed ion exchange resin(1 part AG 50W-X8, 100-200 mesh, hydrogen form, and 2 parts AG 1-X8,100-200 mesh, acetate form) to separate ¹⁴-C-bicabonate from¹⁴C-glucose. The slurry is shaken at room temperature for four hours andthen allowed to settle. An aliquot of the supernatant (0.5 mL) is thencounted in 5 mL scintillation cocktail. The percentage inhibition ofgluconeogenesis in drug-treated rats is calculated by dividing theaverage cpm of ¹⁴C-glucose in samples from drug-treated animals by thosefrom saline-injected animals.

Inhibition ¹⁴C-Glucose production provides evidence that the glucoselowering activity in the Zucker Diabetic Fatty rat (Example K) is due tothe inhibition of gluconeogenesis.

Example M Blood Glucose Lowering in the Streptozotocin-Treated Rat

Diabetes is induced in male Sprague-Dawley rats (250-300 g) byintraperitoneal injection of 55 mg/kg streptozotocin (Sigma ChemicalCo.). Six days later, blood glucose is measured as described in ExampleF. Animals are selected with fed blood glucose values (8 am) between 350and 600 mg/dl, and divided into two groups. One group is dosed orallywith compound (up to about 300 mg/kg) and the second with an equivalentvolume of saline. Food is removed from the animals. Blood glucose ismeasured again after 2 and 4 hours of drug/saline administration.

Example N Oral Absorption Determinations of Prodrugs in the Rat

Prodrugs of the invention are administered to normal, fed rats at 30mg/kg both by intraperitoneal injection and by oral gavage (n=3 rats/compound/route of administration). Rats are subsequently placed inmetabolic cages and urine collected for 24 hours. Parent compound, isquantitated in urine by reverse phase HPLC as described in Example G. Bycomparison of the amount of parent compound excreted in urine followingoral administration to that following intraperitoneal administration,the % oral absorption is calculated for each prodrug.

Example O Chronic Oral Efficacy in the ZDF Rat

To determine the chronic glucose lowering effects of a prodrug of theinvention, ZDF are administered the drug orally for 3 weeks.

Methods: ZDF rats (10 weeks of age) are maintained either on powderedPurina 5008 rat chow (n=10) or the same powdered chow supplemented with1% of the drug (n=8). Blood glucose measurements are made as describedin Example F at baseline and at weekly intervals thereafter for a totalof 3 weeks. Statistical analysis is performed using the Student's ttest.

Example P Identification of the P450 Isozyme Involved in the Activation

Prodrugs are evaluated for human microsome-catalyzed conversion toparent compound in the absence and presence of specific inhibitors ofthree major P450 isozymes: ketoconazole (CYP3A4), furafylline (CYP1A2),and sulfaphenazole (CYP2C9).

Methods: Reaction (0.5 ml@37° C.) consist of 0.2 M KH₂PO₄, 13 mMglucose-6-phosphate, 2.2 mM NADP⁺, 1 unit of glucose-6-phosphatedehydrogenase, 0-2.5 mg/ml human microsomal protein (In VitroTechnologies, In.), 250 μ prodrug, and 0-100 μM P450 isozyme inhibitor.Reactions are stopped by addition of methanol to a concentration of 60%,filtered (0.2 μM filter), and lyophilized. Samples are resuspended inHPLC buffer (10 mM phosphate pH 5.5, 2.5 mM octyl-triethylammonium),loaded onto a YMC C8 HPLC column (250×4.6 mm), and eluted with amethanol gradient to 80%. Formuation of parent drug is confirmed byco-elution with an authentic parent drug standard.

Results: Prodrug is converted readily to parent drug in human livermicrosomes. Ketoconazole will inhibit the formation of parent drugs in adose-dependent fashion. The other inhibitor, fusafylline andsulfaphenazole, will show no significant inhibition. The resultsindicate that CYP3A4 is the primary P450 isoform responsible foractivation of prodrugs in human liver.

While in accordance with the patent statures, description of the variousembodiments and processing conditions have been provided, the scope ofthe invention is not to be limited thereto or thereby. Modifications andalterations of the present invention will be apparent to those skilledin the art without departing from the scope and spirit of the presentinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims, rather than by thespecific examples which have been presented by way of example.

1. A compound of formula (I):

wherein R⁵ is:

wherein: X³, X⁴, and X⁵ are independently selected from the groupconsisting of C and N, wherein one of X³, X⁴, and X⁵ is N; J², J³, J⁴,J⁵, and are independently selected from the group consisting of —H, —NR⁴₂, —CONR⁴ ₂, —CO₂R³, halo, —S(O)₂NR⁴ ₂, —S(O)R³, —SO₂R³, alkyl, alkenyl,alkynyl, alkylenearyl, perhaloalkyl, haloalkyl, aryl, heteroaryl,alkylene-OH, —C(O)R¹¹, —OR¹¹, -alkylene-NR⁴ ₂, -alkylene-CN, —CN,—C(S)NR⁴ ₂, —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, and —NR¹⁸COR²; L isselected from the group consisting of: i) a linking group having 2-4atoms measured by the fewest number of atoms connecting the carbon ofthe aromatic ring and the phosphorus atom and is selected from the groupconsisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,-phenyl-, -pyrimidinyl-, -pyrazinyl-, and -alkynyl-, all of which may beoptionally substituted; and ii) a linking group having 3-4 atomsmeasured by the fewest number of atoms connecting the carbon of thearomatic ring and the phosphorus atom and is selected from the groupconsisting of -alkylenecarbonylamino-, -alkyleneaminocarbonyl-,-alkyleneoxycarbonyl-, and -alkyleneoxy-, and -alkyleneoxyalkylene-, allof which may be optionally substituted; Y is independently selected fromthe group consisting of —O—, and —NR⁶—; when Y is —O—, then R¹ attachedto —O— is independently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocyclic alkylalicyclic where the cyclic moiety contains a carbonate or thiocarbonate,optionally substituted arylalkylene-, —C(R¹)₂OC(O)NR² ₂, —NR²—C(O)—R³,—C(R²)₂—OC(O)R³ —C(R²)₂—O—C(O)OR³, —C(R²)₂OC(O)SR³, -alkylene-S—C(O)R³,-alkylene-S—S-alkylenehydroxy, and -alkylene-S—S—S-alkylenehydroxy, whenone Y is —NR⁶—, and R¹ attached to it is —(CR¹²R¹³)_(n)—C(O)—R¹⁴, thenthe other YR¹ is selected from the group consisting of —NR¹⁵R¹⁶, —OR⁷,and NR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴; or when either Y is independentlyselected from —O—and —NR⁶—, then together R₁ and R¹ are-alkylene-S—S-alkylene- to form a cyclic group, or together R¹ and R¹are

a) V is selected from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl; Z is selected from thegroup of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OC(S)OR³,—CHR²OC(O)SR³, —CHR²OCO₂R³, —OR₂, —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, —SCOR³,—SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹; or together V and Z are connected via an additional 3-5atoms to form a cyclic group, optionally containing 1 heteroatom, saidcyclic group is fused to an aryl group at the beta and gamma position tothe Y adjacent to V; or together Z and W are connected via an additional3-5 atoms to form a cyclic group, optionally containing one heteroatom,and V must be aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; or W and W′ are independently selected from the group of —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or together Wand W′ are connected via an additional 2-5 atoms to form a cyclic group,optionally containing 0-2 heteroatoms, and V must be aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; b) V², W² and W″ areindependently selected from the group of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,—CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR , —CH₂NHaryl, —CH₂aryl; or togetherV² and Z² are connected via an additional 3-5 atoms to form a cyclicgroup containing 5-7 ring atoms, optionally containing 1 heteroatom, andsubstituted with hydroxy, acyloxy, alkyleneoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms from aY attached to phosphorus; c) Z′ is selected from the group of —OH,—OC(O)R³, —OCO₂R³, and —OC(O)SR³; D′ is —H; D″ is selected from thegroup of —H, alkyl, —OR², —OH, and —OC(O)R³; each W³ is independentlyselected from the group consisting of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; p is an integer 2 or 3; with the provisos that: a) V, Z,W, W′ are not all —H and V², Z², W², W″ are not all —H; and R² isselected from the group consisting of R³ and —H; R³ is selected from thegroup consisting of alkyl, aryl, alicyclic, and aralkyl; each R⁴ isindependently selected from the group consisting of —H, alkylene,-alkylenearyl and aryl, or together R⁴ and R⁴ are connected via 2-6atoms, optionally including one heteroatom selected from the groupconsisting of O, N, and S; R⁶ is selected from the group consisting of—H, lower alkyl, acyloxyalkyl, aryl, aralkyl, alkyloxycarbonyloxyalkyl,and lower acyl, or together with R¹² is connected via 1-4 carbon atomsto form a cyclic group; R⁷is lower R³; each R⁹ is independently selectedfrom the group consisting of —H, alkyl, aralkyl, and alicyclic, ortogether R⁹ and R⁹ form a cyclic alkyl group; R¹¹ is selected from thegroup consisting of alkyl, aryl, —NR² ₂, and —OR²; and each R¹² and R¹³is independently selected from the group consisting of H, lower alkyl,lower aryl, lower aralkyl, all optionally substituted, or R¹² and R¹³together are connected via a chain of 2-6 atoms, optionally including 1heteroatom selected from the group consisting of O, N, and S, to form acyclic group; each R¹⁴ is independently selected from the groupconsisting of —OR¹⁷, —N(R¹⁷)₂, —NHR¹⁷, —SR¹⁷, and —NR²OR²⁰; R¹⁵ isselected from the group consisting of —H, lower aralkyl, lower aryl,lower aralkyl, or together with R¹⁶ is connected via 2-6 atoms,optionally including 1 heteroatom selected from the group consisting ofO, N, and S; R¹⁶ is selected from the group consisting of—(CR¹²R¹³)_(n)—C(O)—R¹⁴, —H, lower alkyl, lower aryl, lower aralkyl, ortogether with R¹⁵ is connected via 2-6 atoms, optionally including 1heteroatom selected from the group consisting of O, N, and S; each R¹⁷is independently selected from the group consisting of lower alkyl,lower aryl, and lower aralkyl, or together R¹⁷ and R¹⁷ on N is connectedvia 2-6 atoms, optionally including 1 heteroatom selected from the groupconsisting of O, N, and S; R¹⁸ is selected from the group consisting of—H and lower R³; R¹⁹ is selected from the group consisting of —H, andlower acyl; R²⁰ is selected from the group consisting of —H, lower R³,and —C(O)-(lower R³); n is an integer from 1 to 3; with the provisosthat: 1) when X³, X⁴, or X⁵ is N, then the respective J³, J⁴, or J⁵ isnull; 2) when L is substituted furanyl, then at least one of J², J³, J⁴,and J⁵ is not —H or null; 3) when L is not substituted furanyl, then atleast two of J², J³, J⁴, and J⁵ on formula I(a) or J², J³, J⁴, J⁵, andJ⁶ on formula I(b) are not —H or null; 4) if both Y groups are —NR⁶—,and R¹ and R¹ are not connected to form a cyclic phosphoramidate, thenat least one R¹ is —(CR¹²R¹³)_(n)—C(O)—R¹⁴; 5) R¹ can be selected fromthe lower alkyl only when the other YR¹ is —NR⁶—C(R¹²R¹³)—C(O)—R¹⁴; 6)when L is 1,2-ethynyl, then X³ or X⁵ cannot be N; and pharmaceuticallyacceptable prodrugs and salts thereof.
 2. The compounds of claim 1wherein R⁵ is substituted pyridinyl. 3.-8. (canceled)
 9. The compoundsof claim 1 wherein L is selected from the group consisting of: i)2,5-furanyl, 2,5-thienyl, 2,6-pyridyl, 2,5-oxazolyl, 5,2-oxazolyl,2,4-oxazolyl, 4,2-oxazolyl, 2,4-imidazolyl, 2,6-pyrimidinyl,2,6-pyrazinyl, 1,3-phenyl; ii) 1,2-ethynyl; and iii) a linking grouphaving 3 atoms measured by the fewest number of atoms connecting thecarbon of the aromatic ring and the phosphorus atom and is selected fromthe group consisting of -alkylenecarbonylamino-,-alkyleneaminocarbonyl-, -alkyleneoxycarbonyl-, and-alkyleneoxyalkylene-.
 10. The compounds of claim 9 wherein L isselected from the group consisting of: i) 2,5-furanyl, 2,5-thienyl,2,6-pyridyl, 2,5-oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl,2,4-imidazolyl, 2,6-pyrimidinyl, 2,6-pyrazinyl, 1,3-phenyl; and ii)1,2-ethynyl.
 11. The compounds of claim 9 wherein L is selected from thegroup consisting of: i) 2,5-furanyl, 2,6-pyridyl, 2,5-oxazolyl,2,4-imidazolyl, 1,3-phenyl; ii) 1,2-ethynyl; and iii) a linking grouphaving 3 atoms measured by the fewest number of atoms connecting thecarbon of the aromatic ring and the phosphorus atom and is selected fromthe group consisting of -methylenecarbonylamino-,-methyleneaminocarbonyl-, -methyleneoxycarbonyl-, and-methyleneoxymethylene-.
 12. The compounds of claim 11 wherein L isselected from the group consisting of 2,5-furanyl, methyleneoxycarbonyl,methyleneoxymethylene, and methyleneaminocarbonyl.
 13. The compounds ofclaim 12 wherein L is 2,5-furanyl.
 14. The compounds of claim 1 whereinX⁴ and X⁵ are C.
 15. The compounds of claim 1 wherein J², J³, J⁴, J⁵,and J⁶ are independently selected from the group consisting of H, —NR⁴₂, —C(O)NR⁴ ₂, —CO₂R³, halo, —SO₂NR⁴ ₂, lower alkyl, lower alkenyl,lower alkynyl, lower perhaloalkyl, lower haloalkyl, lower aryl, loweralkylaryl, lower alkylene-OH, —OR¹¹, —CR² ₂NR⁴ ₂, —CN, —C(S)NR⁴ ₂, —OR²,—SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, —NR¹⁸C(O)R² and —CR² ₂CN.
 16. Thecompounds of claim 12 wherein J², J³, J⁴, J⁵, and J⁶ are independentlyselected from the group consisting of —H, —NO₂, lower alkyl, loweralkylaryl, lower alkoxy, lower perhaloalkyl, halo, —CH₂NHR⁴, —C(O)NR⁴ ₂,—S(O)₂NHR⁴, —OH, —NH₂, and —NHC(O)R².
 17. The compounds of claim 1,where both Y groups are —O—.
 18. The compounds of claim 1, where both Ygroups are —NR⁶—.
 19. The compounds of claim 1 where one Y is —NR⁶—, andone Y is —O—.
 20. The compounds of claim 1 wherein each YR¹ is —OH. 21.The compounds of claim 1 wherein R¹ and R¹ together are

Z′ is selected from the group of —OH, —OC(O)R³, —OCO₂R³, and —OC(O)SR³;D′ is —H; D″ is selected from the group of —H, alkyl, —OR², —OH, and—OC(O)R³; and each W³ is independently selected from the groupconsisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl.
 22. Thecompounds of claim 1 wherein R¹ and R¹ together are

V is selected from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl; Z is selected from thegroup of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OC(S)OR³,—CHR²OC(O)SR³, —CHR²OCO₂R³, —OR², —SR, —CHR²N₃, —CH₂aryl, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, —SCOR³,—SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹; or together V and Z are connected via an additional 3-5atoms to form a cyclic group, optionally containing 1 heteroatom, saidcyclic group is fused to an aryl group at the beta and gamma position tothe Y adjacent to V; or together Z and W are connected via an additional3-5 atoms to form a cyclic group, optionally containing one heteroatom,and V must be aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; or W and W′ are independently selected from the group of —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or together Wand W′ are connected via an additional 2-5 atoms to form a cyclic group,optionally containing 0-2 heteroatoms, and V must be aryl, substitutedaryl, heteroaryl, or substituted heteroaryl.
 23. The compounds of claim1 wherein R¹ and R¹ together are

V², W² and W″ are independently selected from the group of —H, alkyl,aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, 1-alkenyl, and 1-alkynyl; Z²is selected from the group of—CHR²OH, —CHR²OC(O)R, —CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³,—CHR²OC(S)OR³, —CH(aryl)OH, —CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR²,—CH₂NHaryl, —CH₂aryl; or together V² and Z² are connected via anadditional 3-5 atoms to form a cyclic group containing 5-7 ring atoms,optionally containing 1 heteroatom, and substituted with hydroxy,acyloxy, alkyleneoxycarbonyloxy, or aryloxycarbonyloxy attached to acarbon atom that is three atoms from a Y attached to phosphorus.
 24. Thecompounds of claim 1 wherein when both Y groups are —O—, then R¹attached to —O— is optionally substituted aryl.
 25. The compounds ofclaim 1 wherein when both Y groups are —O—, then R¹ is independentlyselected from the group consisting of optionally substituted aralkyl.26. The compounds of claim 1 wherein both Y groups are —O—, and at leastone R¹ is selected from the group consisting of —C(R²)₂—OC(O)R³, and—C(R²)₂—OC(O)OR³.
 27. The compounds of claim 1 wherein at least one Y is—O—, and together R¹ and R¹ are

a) V is selected from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl; Z is selected from thegroup of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OC(S)OR³,—CHR²OC(O)SR³, —CHR²OCO₂R³, —OR², —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, —SCOR³,—SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹; or together V and Z are connected via an additional 3-5atoms to form a cyclic group, optionally containing 1 heteroatom, saidcyclic group is fused to an aryl group at the beta and gamma position tothe Y adjacent to V; or together Z and W are connected via an additional3-5 atoms to form a cyclic group, optionally containing one heteroatom,and V must be aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; or W and W′ are independently selected from the group of —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or together Wand W′ are connected via an additional 2-5 atoms to form a cyclic group,optionally containing 0-2 heteroatoms, and V must be aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; b) V², W² and W″ areindependently selected from the group of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; Z² is selected from the group of —CHR₂OH, —CHR²OC(O)R³,—CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR², —CH₂NHaryl, —CH₂aryl; or togetherV² and Z² are connected via an additional 3-5 atoms to form a cyclicgroup containing 5-7 ring atoms, optionally containing 1 heteroatom, andsubstituted with hydroxy, acyloxy, alkyleneoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms from aY attached to phosphorus; c) Z′ is selected from the group of —OH,—OC(O)R³, —OCO₂R³, and —OC(O)SR³; D′ is —H; D″ is selected from thegroup of —H, alkyl, —OR², —OH, and —OC(O)R³; each W³ is independentlyselected from the group consisting of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; p is an integer 2 or 3; with the provisos that: a) V, Z,W, W′ are not all —H and V², Z², W², W″ are not all —H ; and b) both Ygroups are not —NR⁶—; R² is selected from the group consisting of R³ and—H; R³ is selected from the group consisting of alkyl, aryl, alicyclic,and aralkyl; R⁶ is selected from the group consisting of —H, and loweralkyl.
 28. The compounds of claim 1 wherein one Y is —O—, and R¹ isoptionally substituted aryl; and the other Y is —NR⁶—, where R¹ attachedto said —NR⁶- is selected from the group consisting of —C(R⁴)₂C(O)OR³,and —C(R²)₂C(O)OR³.
 29. The compounds of claim 1 wherein J², J³, J⁴, J⁵,and J⁶ are independently selected from the group consisting of —H, —NR⁴₂, —CONR⁴ ₂, —CO₂R³, halo, —SO₂NR⁴ ₂, lower alkyl, lower alkenyl, loweralkylenearyl, lower alkynyl, lower perhaloalkyl, lower haloalkyl, loweraryl, lower alkylene-OH, 13 OR¹¹, —CR² ₂NR⁴ ₂, —CN, —C(S)NR⁴ ₂, —OR²,—SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, —NR¹⁸COR², —CR² ₂CN; L is selected fromthe group consisting of i) 2,5-furanyl, 2,5-thienyl, 1,3-phenyl,2,6-pyridyl, 2,5-oxazolyl, 5,2-oxazolyl, 2,4-oxazolyl, 4,2-oxazolyl,2,4-imidazolyl, 2,6-pyrimidinyl, 2,6-pyrazinyl; ii) 1,2-ethynyl; andiii) a linking group having 3 atoms measured by the fewest number ofatoms connecting the carbon of the aromatic ring and the phosphorus atomand is selected from the group consisting of alkylenecarbonylamino-,-alkyleneaminocarbonyl-, -alkyleneoxycarbonyl-, and-alkyleneoxyalkylene-; when both Y groups are —O—, then R¹ isindependently selected from the group consisting of optionallysubstituted aryl, optionally substituted benzyl, —C(R²)₂OC(O)R³,—C(R²)₂OC(O)OR³, and —H; or when one Y is —O—, then R¹ attached to —O—is optionally substituted aryl; and the other Y is —NR⁶—, then R¹attached to —NR⁶— is selected from the group consisting of—C(R⁴)₂C(O)OR³, and —C(R²)₂C(O)OR³; or when Y is —O— or —NR⁶—, thentogether R¹ and R¹ are

a) V is selected from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl; Z is selected from thegroup of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OC(S)OR³,—CHR²OC(O)SR³, —CHR²OCO₂R³, —OR², —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, —SCOR³,—SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹; or together V and Z are connected via an additional 3-5atoms to form a cyclic group, optionally containing 1 heteroatom, saidcyclic group is fused to an aryl-group at the beta and gamma position tothe Y adjacent to V; or together Z and W are connected via an additional3-5 atoms to form a cyclic group, optionally containing one heteroatom,and V must be aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; or W and W′ are independently selected from the group of —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or together Wand W′ are connected via an additional 2-5 atoms to form a cyclic group,optionally containing 0-2 heteroatoms, and V must be aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; b) V², W² and W″ areindependently selected from the group of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,—CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR², —CH₂NHaryl, —CH₂aryl; or togetherV² and Z² are connected via an additional 3-5 atoms to form a cyclicgroup containing 5-7 ring atoms, optionally containing 1 heteroatom, andsubstituted with hydroxy, acyloxy, alkyleneoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms from aY attached to phosphorus; c) Z′ is selected from the group of —OH,—OC(O)R³, —OCO₂R³, and —OC(O)SR³; D′ is —H; D″ is selected from thegroup of —H, alkyl, —OR², —OH, and —OC(O)R³; each W³ is independentlyselected from the group consisting of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; p is an integer 2 or 3; with the provisos that: a) V, Z,W, W′ are not all —H and V², Z², W², W″ are not all —H; and alicyclic;and b) both Y groups are not —NR⁶—; R² is selected from the groupconsisting of R³ and —H; R³ is selected from the group consisting ofalkyl, aryl, alicyclic, and aralkyl; R⁶ is selected from the groupconsisting of —H, and lower alkyl.
 30. (canceled)
 31. The compounds ofclaim 1 wherein one Y is —NR⁶—, and R¹ attached to it is—(CR¹²R¹³)_(n)—C(O)—R¹⁴, then the other YR¹ is selected from the groupconsisting of —NR¹⁵R¹⁶, —OR⁷, and NR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴.
 32. Thecompounds of claim 31 wherein the other YR¹ is —OR⁷.
 33. The compoundsof claim 1 that are of the formula:


34. A method of treating complications of diabetes or cardiovasculardiseases associated with increased insulin levels in an animal whichcomprises administering to an animal suffering from complications ofdiabetes or cardiovascular diseases associated with increased insulinlevels a pharmaceutically effective amount of a compound of formula (I):

wherein R⁵ is:

wherein: X³, X⁴, and X⁵ are independently selected from the groupconsisting of C and N, wherein one of X³, X⁴, and X⁵ is N; J², J³, J⁴,J⁵, and J⁶ are independently selected from the group consisting of —H,—NR⁴ ₂, —CONR⁴ ₂, —CO₂R³, halo, —S(O)₂NR⁴ ₂, —S(O)R³, —SO₂R³, alkyl,alkenyl, alkynyl, alkylenearyl, perhaloalkyl, haloalkyl, aryl,heteroaryl, alkylene-OH, —C(O)R¹¹, —OR¹¹, -alkylene-NR⁴ ₂, -alkylene-CN,—CN, —C(S)NR⁴ ₂, —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, and —NR¹⁸COR²; Lis selected from the group consisting of: i) a linking group having 2-4atoms measured by the fewest number of atoms connecting the carbon ofthe aromatic ring and the phosphorus atom and is selected from the groupconsisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,-phenyl-, -pyrimidinyl-, -pyrazinyl-, and -alkynyl-, all of which may beoptionally substituted; and ii) a linking group having 3-4 atomsmeasured by the fewest number of atoms connecting the carbon of thearomatic ring and the phosphorus atom and is selected from the groupconsisting of -alkylenecarbonylamino-, -alkyleneaminocarbonyl-,-alkyleneoxycarbonyl-, -alkyleneoxy-, -alkylenethio-,-alkylenecarbonyloxy-, -alkylene-S(O)—, -alkylene-S(O)₂—, and-alkyleneoxyalkylene-, all of which may be optionally substituted; Y isindependently selected from the group consisting of —O—, and —NR⁶—; whenY is —O—, then R¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, optionally substituted aryl, optionallysubstituted alicyclic where the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted arylalkylene-, —C(R²)₂OC(O)NR² ₂,—NR²—C(O)—R³, —C(R²)₂—OC(O)R³—C(R²)₂—O—C(O)OR³, —C(R²)₂OC(O)SR³,-alkylene-S—C(O)R³, -alkylene-S—S-alkylenehydroxy, and-alkylene-S—S—S-alkylenehydroxy, when one Y is —NR⁶—, and R¹ attached toit is —(CR¹²R¹³)_(n)—C(O)—R¹⁴, then the other YR¹ is selected from thegroup consisting of —NR¹⁵R¹⁶, —OR⁷, and NR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴; orwhen either Y is independently selected from —O— and —NR⁶—, thentogether R¹ and R¹ are -alkylene-S—S-alkylene- to form a cyclic group,or together R¹ and R¹ are

a) V is selected from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl; Z is selected from thegroup of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OC(S)OR³,—CHR²OC(O)SR³, —CHR²OCO₂R³, —OR², —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, —SCOR³,—SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹; or together V and Z are connected via an additional 3-5atoms to form a cyclic group, optionally containing 1 heteroatom, saidcyclic group is fused to an aryl group at the beta and gamma position tothe Y adjacent to V; or together Z and W are connected via an additional3-5 atoms to form a cyclic group, optionally containing one heteroatom,and V must be aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; or W and W′ are independently selected from the group of —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or together Wand W′ are connected via an additional 2-5 atoms to form a cyclic group,optionally containing 0-2 heteroatoms, and V must be aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; b) V2, W2 and W″ areindependently selected from the group of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,—CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR², —CH₂NHaryl, —CH₂aryl; or togetherV² and Z² are connected via an additional 3-5 atoms to form a cyclicgroup containing 5-7 ring atoms, optionally containing 1 heteroatom, andsubstituted with hydroxy, acyloxy, alkyleneoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms from aY attached to phosphorus; c) Z′ is selected from the group of —OH,—OC(O)R³, —OCO₂R³, and —OC(O)SR³; D′ is —H; D″ is selected from thegroup of —H, alkyl, —OR², —OH, and —OC(O)R³; each W³ is independentlyselected from the group consisting of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; p is an integer 2 or 3; with the provisos that: a) V, Z,W, W′ are not all —H and V², Z², W², W″ are not all —H ; and R² isselected from the group consisting of R³ and —H; R³ is selected from thegroup consisting of alkyl, aryl, alicyclic, and aralkyl; each R⁴ isindependently selected from the group consisting of —H, alkylene,-alkylenearyl and aryl, or together R⁴ and R⁴ are connected via 2-6atoms, optionally including one heteroatom selected from the groupconsisting of O, N, and S; R⁶ is selected from the group consisting of—H, lower alkyl, acyloxyalkyl, aryl, aralkyl, alkyloxycarbonyloxyalkyl,and lower acyl, or together with R¹² is connected via 1-4 carbon atomsto form a cyclic group; R⁷ is lower R³; each R⁹ is independentlyselected from the group consisting of —H, alkyl, aralkyl, and alicyclic,or together R⁹ and R⁹ form a cyclic alkyl group; R¹¹ is selected fromthe group consisting of alkyl, aryl, —NR² ₂, and —OR²; and each R¹² andR¹³ is independently selected from the group consisting of H, loweralkyl, lower aryl, lower aralkyl, all optionally substituted, or R¹² andR¹³ together are connected via a chain of 2-6 atoms, optionallyincluding 1 heteroatom selected from the group consisting of O, N, andS, to form a cyclic group; each R¹⁴ is independently selected from thegroup consisting of —OR¹⁷, —N(R¹⁷)₂, —NHR¹⁷—SR¹⁷, and —NR²OR²⁰; R¹⁵ isselected from the group consisting of —H, lower aralkyl, lower aryl,lower aralkyl, or together with R¹⁶ is connected via 2-6 atoms,optionally including 1 heteroatom selected from the group consisting ofO, N, and S; R¹⁶ is selected from the group consisting of—CR¹²R¹³)_(n)—C(O)—R¹⁴, —H, lower alkyl, lower aryl, lower aralkyl, ortogether with R¹⁵ is connected via 2-6 atoms, optionally including 1heteroatom selected from the group consisting of O N, and S; each R¹⁷ isindependently selected from the group consisting of lower alkyl, loweraryl, and lower aralkyl, or together R¹⁷ and R¹⁷ on N is connected via2-6 atoms, optionally including 1 heteroatom selected from the groupconsisting of O, N, and S; R¹⁸ is selected from the group consisting of—H and lower R³; R¹⁹ is selected from the group consisting of —H, andlower acyl; R²⁰ is selected from the group consisting of —H, lower R³,and —C(O)-(lower R³); n is an integer from 1 to 3; with the provisosthat: 1) when X³, X⁴, or X⁵ is N, then the respective J³, J⁴, or J⁵ isnull; 2) if both Y groups are —NR⁶—, and R¹ and R¹ are not connected toform a cyclic phosphoramidate, then at least one R¹ is—(CR¹²R¹³)_(n)—C(O)—R¹⁴; 3) R¹ can be selected from the lower alkyl onlywhen the other YR¹ is —NR⁶—C(R¹²R¹³)_(n)—C(O)—R¹⁴; and pharmaceuticallyacceptable prodrugs and salts thereof
 35. A method of treating diabetes,by administering to patient a pharmaceutically effective amount of anFBPase inhibitor of Formula I:

wherein R⁵ is:

wherein: X³, X⁴, and X⁵ are independently selected from the groupconsisting of C and N, wherein one of X³, X⁴, and X⁵ is N; J¹, J³, J⁴,J⁵, and J⁶ are independently selected from the group consisting of —H,—NR⁴ ₂, —CONR⁴ ₂, —CO₂R³, halo, —S(O)₂NR⁴ ₂, —S(O)R³, —SO₂R³, alkyl,alkenyl, alkynyl, alkylenearyl, perhaloalkyl, haloalkyl, aryl,heteroaryl, alkylene-OH, —C(O)R¹¹, —OR¹¹, -alkylene-NR⁴ ₂, -alkylene-CN,—CN, —C(S)NR⁴ ₂, —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, and —NR¹⁸COR²; Lis selected from the group consisting of: i) a linking group having 2-4atoms measured by the fewest number of atoms connecting the carbon ofthe aromatic ring and the phosphorus atom and is selected from the groupconsisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,-phenyl-, -pyrimidinyl-, -pyrazinyl-, and -alkynyl-, all of which may beoptionally substituted; and ii) a linking group having 3-4 atomsmeasured by the fewest number of atoms connecting the carbon of thearomatic ring and the phosphorus atom and is selected from the groupconsisting of -alkylenecarbonylamino-, -alkyleneaminocarbonyl-,-alkyleneoxycarbonyl-, -alkyleneoxy-furanyl-, -alkylenethio-,-alkylenecarbonyloxy-, -alkylene-S(O)—, -alkylene-S(O)₂—, and-alkyleneoxyalkylene-, all of which may be optionally substituted; Y isindependently selected from the group consisting of —O—, and —NR⁶—; whenY is —O—, then R¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, optionally substituted aryl, optionallysubstituted alicyclic where the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted arylalkylene-, —C(R²)₂OC(O)NR₂,—NR²—C(O)—R³, —C(R²)₂—OC(O)R³, —C(R²)₂—O—C(O)OR³, —C(R²)₂OC(O)SR³,-alkylene-S—C(O)R³, -alkylene-S—S-alkylenehydroxy, and-alkylene-S—S—S-alkylenehydroxy, when one Y is —NR⁶—, and R¹ attached toit is —(CR¹²R¹³)_(n)—C(O)—R¹⁴, then the other YR¹ is selected from thegroup consisting of —NR¹⁵R¹⁶, —OR⁷, and NR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴; orwhen either Y is independently selected from —O— and —NR⁶—, thentogether R¹ and R¹ are -alkylene-S—S-alkylene- to form a cyclic group,or together R¹ and R¹ are

a) V is selected from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl; Z is selected from thegroup of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHROC(S)OR ,—CHR²OC(O)SR³, —CHR²OCO₂R³, —OR², —SR², —CHR²N₃, —CH₂aryl, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂R³, —SCOR³,—SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl, —(CH₂)_(p)—OR¹⁹, and—(CH₂)_(p)—SR¹⁹; or together V and Z are connected via an additional 3-5atoms to form a cyclic group, optionally containing 1 heteroatom, saidcyclic group is fused to an aryl group at the beta and gamma position tothe Y adjacent to V; or together Z and W are connected via an additional3-5 atoms to form a cyclic group, optionally containing one heteroatom,and V must be aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; or W and W′ are independently selected from the group of —H,alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkenyl and 1-alkynyl and —R⁹; or together Wand W′ are connected via an additional 2-5 atoms to form a cyclic group,optionally containing 0-2 heteroatoms, and V must be aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; b) V², W² and W″ areindependently selected from the group of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; Z² is selected from the group of —CHR²OH, —CHR²OC(O)R³,—CHR²OC(S)R³, —CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³, —CH(aryl)OH,—CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —SR², —CH₂NHaryl, —CH₂aryl; or togetherV² and Z² are connected via an additional 3-5 atoms to form a cyclicgroup containing 5-7 ring atoms, optionally containing 1 heteroatom, andsubstituted with hydroxy, acyloxy, alkyleneoxycarbonyloxy, oraryloxycarbonyloxy attached to a carbon atom that is three atoms from aY attached to phosphorus; c) Z′ is selected from the group of —OH,—OC(O)R³, —OCO₂R³, and —OC(O)SR³; D′ is —H; D″ is selected from thegroup of —H, alkyl, —OR², —OH, and —OC(O)R³; each W³ is independentlyselected from the group consisting of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl,and 1-alkynyl; p is an integer 2 or 3; with the provisos that: a) V, Z,W, W′ are not all —H and V², Z², W², W″ are not all —H; and R² isselected from the group consisting of R³ and —H; R³ is selected from thegroup consisting of alkyl, aryl, alicyclic, and aralkyl; each R⁴ isindependently selected from the group consisting of —H, alkylene,-alkylenearyl and aryl, or together R⁴ and R⁴ are connected via 2-6atoms, optionally including one heteroatom selected from the groupconsisting of O, N, and S; R⁶ is selected from the group consisting of—H, lower alkyl, acyloxyalkyl, aryl, aralkyl, alkyloxycarbonyloxyalkyl,and lower acyl, or together with R¹² is connected via 1-4 carbon atomsto form a cyclic group; R⁷ is lower R³; each R⁹ is independentlyselected from the group consisting of —H, alkyl, aralkyl, and alicyclic,or together R⁹ and R⁹ form a cyclic alkyl group; R¹¹ is selected fromthe group consisting of alkyl, aryl, —NR² ₂, and —OR²; and each R¹² andR¹³ is independently selected from the group consisting of H, loweralkyl, lower aryl, lower aralkyl, all optionally substituted, or R¹² andR¹³ together are connected via a chain of 2-6 atoms, optionallyincluding 1 heteroatom selected from the group consisting of O, N, andS, to form a cyclic group; each R¹⁴ is independently selected from thegroup consisting of —OR¹⁷, —N(R¹⁷)₂, —NHR¹⁷, —SR¹⁷, and —NR²OR²⁰; R¹⁵ isselected from the group consisting of —H, lower aralkyl, lower aryl,lower aralkyl, or together with R¹⁶ is connected via 2-6 atoms,optionally including 1 heteroatom selected from the group consisting ofO, N, and S; R¹⁶ is selected from the group consisting of—CR¹²R¹³)_(n)—C(O)—R¹⁴, —H, lower alkyl, lower aryl, lower aralkyl, ortogether with R¹⁵ is connected via 2-6 atoms, optionally including 1heteroatom selected from the group consisting of O, N, and S; each R¹⁷is independently selected from the group consisting of lower alkyl,lower aryl, and lower aralkyl, or together R¹⁷ and R¹⁷ on N is connectedvia 2-6 atoms, optionally including 1 heteroatom selected from the groupconsisting of O, N, and S; R¹⁸ is selected from the group consisting of—H and lower R³; R¹⁹ is selected from the group consisting of —H, andlower acyl; R²⁰ is selected from the group consisting of —H, lower R³,and —C(O)-(lower R³); n is an integer from 1 to 3; with the provisosthat: 1) when X³, X⁴, or X⁵ is N, then the respective J³, J⁴, or J⁵ isnull; 2) if both Y groups are —NR⁶—, and R¹ and R¹ are not connected toform a cyclic phosphoramidate, then at least one R¹ is—(CR¹²R¹³)_(n)—C(O)—R¹⁴; 3) R¹ can be selected from the lower alkyl onlywhen the other YR¹ is —NR⁶—C(R¹²R¹³)_(n)—C(O)—R¹⁴; and pharmaceuticallyacceptable prodrugs and salts thereof.
 36. A method of treating glycogenstorage diseases, by administering to a patient a pharmaceuticallyeffective amount of an FBPase inhibitor of formula I:

wherein R⁵ is:

wherein: X³, X⁴, and X⁵ are independently selected from the groupconsisting of C and N, wherein one of X³, X⁴, and X⁵ is N; J², J³, J⁴,J⁵, and J⁶ are independently selected from the group consisting of —H,—NR⁴ ₂, —CONR⁴ ₂, —CO₂R³, halo, —S(O)₂NR⁴ ₂, —S(O)R³, —SO₂R³, alkyl,alkenyl, alkynyl, alkylenearyl, perhaloalkyl, haloalkyl, aryl,heteroaryl, alkylene-OH, —C(O)R¹¹, —OR¹¹, -alkylene-NR⁴ ₂, -alkylene-CN,—CN, —C(S)NR⁴ ₂, —OR², —SR², —N₃, —NO₂, —NHC(S)NR⁴ ₂, and —NR¹⁸COR²; Lis selected from the group consisting of: i) a linking group having 2-4atoms measured by the fewest number of atoms connecting the carbon ofthe aromatic ring and the phosphorus atom and is selected from the groupconsisting of -furanyl-, -thienyl-, -pyridyl-, -oxazolyl-, -imidazolyl-,-phenyl-, -pyrimidinyl-, -pyrazinyl-, and -alkynyl-, all of which may beoptionally substituted; and ii) a linking group having 3-4 atomsmeasured by the fewest number of atoms connecting the carbon of thearomatic ring and the phosphorus atom and is selected from the groupconsisting of -alkylenecarbonylamino-, -alkyleneaminocarbonyl-,-alkyleneoxycarbonyl-, -alkyleneoxy-, -alkylenethio-,-alkylenecarbonyloxy-, -alkylene-S(O)—, -alkylene-S(O)₂—, and-alkyleneoxyalkylene-, all of which may be optionally substituted; Y isindependently selected from the group consisting of —O—, and —NR⁶—; whenY is —O—, then R¹ attached to —O— is independently selected from thegroup consisting of —H, alkyl, optionally substituted aryl, optionallysubstituted alicyclic where the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted arylalkylene-, —C(R²)₂OC(O)NR² ₂,—NR²—C(O)—R³, —C(R²)₂—OC(O)R³, —C(R²)₂—O—C(O)OR³, —C(R²)₂OC(O)SR³,-alkylene-S—C(O)R³, -alkylene-S—S-alkylenehydroxy, and-alkylene-S—S—S-alkylenehydroxy, when one Y is —NR⁶—, and R¹ attached toit is —(CR¹²R¹³)_(n)—C(O)—R¹⁴, then the other YR¹ is selected from thegroup consisting of —NR¹⁵R¹⁶, —OR⁷, and NR⁶—(CR¹²R¹³)_(n)—C(O)—R¹⁴; orwhen either Y is independently selected from —O— and —NR⁶—, thentogether R¹ and R¹ are -alkylene-S—S-alkylene- to form a cyclic group,or together R¹ and R¹ are

a) V is selected from the group of aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkynyl and 1-alkenyl; Z is selected from thegroup of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³, —CHR²OC(S)OR³,—CHR²OC(O)SR³, —CHR²OCO₂R³, —OR², —SR², —CHR^(N) ₃, —CH₂aryl,—CH(aryl)OH, —CH(CH═CR² ₂)OH, —CH(C≡CR²)OH, —R², —NR² ₂, —OCOR³,—OCO₂R³, —SCOR³, —SCO₂R³, —NHCOR², —NHCO₂R³, —CH₂NHaryl,—(CH₂)_(p)—OR¹⁹, and —(CH₂)_(p)—SR¹⁹; or together V and Z are connectedvia an additional 3-5 atoms to form a cyclic group, optionallycontaining 1 heteroatom, said cyclic group is fused to an aryl group atthe beta and gamma position to the Y adjacent to V; or together Z and Ware connected via an additional 3-5 atoms to form a cyclic group,optionally containing one heteroatom, and V must be aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; or W and W′ areindependently selected from the group of —H, alkyl, aralkyl, alicyclic,aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyland 1-alkynyl and —R⁹; or together W and W′ are connected via anadditional 2-5 atoms to form a cyclic group, optionally containing 0-2heteroatoms, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; b) V², W² and W″ are independently selected fromthe group of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; Z² isselected from the group of —CHR²OH, —CHR²OC(O)R³, —CHR²OC(S)R³,—CHR²OCO₂R³, —CHR²OC(O)SR³, —CHR²OC(S)OR³, —CH(aryl)OH, —CH(CH═CR² ₂)OH,—CH(C≡CR²)OH, —SR², —CH₂NHaryl, —CH₂aryl; or together V² and Z² areconnected via an additional 3-5 atoms to form a cyclic group containing5-7 ring atoms, optionally containing 1 heteroatom, and substituted withhydroxy, acyloxy, alkyleneoxycarbonyloxy, or aryloxycarbonyloxy attachedto a carbon atom that is three atoms from a Y attached to phosphorus; c)Z¹ is selected from the group of —OH, —OC(O)R³, —OCO₂R³, and —OC(O)SR³;D′ is —H; D″ is selected from the group of —H, alkyl, —OR², —OH, and—OC(O)R³; each W³ is independently selected from the group consisting of—H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, 1-alkenyl, and 1-alkynyl; p is an integer 2 or3; with the provisos that: a) V, Z, W, W′ are not all —H and V², Z², W²,W″ are not all —H; and R² is selected from the group consisting of R³and —H; R³ is selected from the group consisting of alkyl, aryl,alicyclic, and aralkyl; each R⁴ is independently selected from the groupconsisting of —H, alkylene, -alkylenearyl and aryl, or together R⁴ andR⁴ are connected via 2-6 atoms, optionally including one heteroatomselected from the group consisting of O, N, and S; R⁶ is selected fromthe group consisting of —H, lower alkyl, acyloxyalkyl, aryl, aralkyl,alkyloxycarbonyloxyalkyl, and lower acyl, or together with R¹² isconnected via 1-4 carbon atoms to form a cyclic group; R⁷ is lower R³;each R⁹ is independently selected from the group consisting of —H,alkyl, aralkyl, and alicyclic, or together R⁹ and R⁹ form a cyclic alkylgroup; R¹¹ is selected from the group consisting of alkyl, aryl, —NR² ₂,and —OR²; and each R¹² and R¹³ is independently selected from the groupconsisting of H, lower alkyl, lower aryl, lower aralkyl, all optionallysubstituted, or R¹² and R¹³ together are connected via a chain of 2-6atoms, optionally including 1 heteroatom selected from the groupconsisting of O, N, and S, to form a cyclic group; each R¹⁴ isindependently selected from the group consisting of —OR¹⁷, —N(R¹⁷)₂,—NHR¹⁷, —SR¹⁷, and —NR²OR²⁰; R¹⁵ is selected from the group consistingof —H, lower aralkyl, lower aryl, lower aralkyl, or together with R¹⁶ isconnected via 2-6 atoms, optionally including 1 heteroatom selected fromthe group consisting of O, N, and S; R¹⁶ is selected from the groupconsisting of —(CR¹²R¹³)_(n)—C(O)—R¹⁴, —H, lower alkyl, lower aryl,lower aralkyl, or together with R¹⁵ is connected via 2-6 atoms,optionally including 1 heteroatom selected from the group consisting ofO, N, and S; each R¹⁷ is independently selected from the groupconsisting of lower alkyl, lower aryl, and lower aralkyl, or togetherR¹⁷ and R¹⁷ on N is connected via 2-6 atoms, optionally including 1heteroatom selected from the group consisting of O, N, and S; R¹⁸ isselected from the group consisting of —H and lower R³; R¹⁹ is selectedfrom the group consisting of —H, and lower acyl; R²⁰ is selected fromthe group consisting of —H, lower R³, and —C(O)-(lower R³); n is aninteger from 1 to 3; with the provisos that: 1) when X³, X⁴, or X⁵ is N,then the respective J³, J⁴, or J⁵ is null; 2) when G², G³, or G⁴ is O orS, then the respective J², J³, or J⁴ is null; 3) when G³ or G⁴ is N,then the respective J³ or J⁴ is not halogen or a group directly bondedto G³ or G⁴ via a heteroatom; 4) if both Y groups are —NR⁶—, and R¹ andR¹ are not connected to form a cyclic phosphoramidate, then at least oneR¹ is —(CR¹²R¹³)_(n)—C(O)—R¹⁴; 5) R¹ can be selected from the loweralkyl only when the other YR¹ is —NR⁶—C(R¹²R¹³)_(n)—C(O)—R¹⁴; andpharmaceutically acceptable prodrugs and salts thereof.